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Article ; Online: Immunomodulatory Effects of Radiotherapy

Sharda Kumari / Shibani Mukherjee / Debapriya Sinha / Salim Abdisalaam / Sunil Krishnan / Aroumougame Asaithamby

International Journal of Molecular Sciences, Vol 21, Iss 8151, p

2020 Volume 8151

Abstract: Radiation therapy (RT), an integral component of curative treatment for many malignancies, can be administered via an increasing array of techniques. In this review, we summarize the properties and application of different types of RT, specifically, ... ...

Abstract	Radiation therapy (RT), an integral component of curative treatment for many malignancies, can be administered via an increasing array of techniques. In this review, we summarize the properties and application of different types of RT, specifically, conventional therapy with x-rays, stereotactic body RT, and proton and carbon particle therapies. We highlight how low-linear energy transfer (LET) radiation induces simple DNA lesions that are efficiently repaired by cells, whereas high-LET radiation causes complex DNA lesions that are difficult to repair and that ultimately enhance cancer cell killing. Additionally, we discuss the immunogenicity of radiation-induced tumor death, elucidate the molecular mechanisms by which radiation mounts innate and adaptive immune responses and explore strategies by which we can increase the efficacy of these mechanisms. Understanding the mechanisms by which RT modulates immune signaling and the key players involved in modulating the RT-mediated immune response will help to improve therapeutic efficacy and to identify novel immunomodulatory drugs that will benefit cancer patients undergoing targeted RT.
Keywords	radiation therapy ; charged particle therapy ; carbon ion therapy ; clustered DNA damage ; immune signaling ; cancer vaccines ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	616
Language	English
Publishing date	2020-10-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Tumor treating fields cause replication stress and interfere with DNA replication fork maintenance: Implications for cancer therapy.

Karanam, Narasimha Kumar / Ding, Lianghao / Aroumougame, Asaithamby / Story, Michael D

Translational research : the journal of laboratory and clinical medicine

2019 Volume 217, Page(s) 33–46

Abstract: Tumor treating fields (TTFields) is a noninvasive physical modality of cancer therapy that applies low-intensity, intermediate frequency, and alternating electric fields to a tumor. Interference with mitosis was the first mechanism describing the effects ...

Abstract	Tumor treating fields (TTFields) is a noninvasive physical modality of cancer therapy that applies low-intensity, intermediate frequency, and alternating electric fields to a tumor. Interference with mitosis was the first mechanism describing the effects of TTFields on cancer cells; however, TTFields was shown to not only reduce the rejoining of radiation-induced DNA double-strand breaks (DSBs), but to also induce DNA DSBs. The mechanism(s) by which TTFields generates DNA DSBs is related to the generation of replication stress including reduced expression of the DNA replication complex genes MCM6 and MCM10 and the Fanconi's Anemia pathway genes. When markers of DNA replication stress as a result of TTFields exposure were examined, newly replicated DNA length was reduced with TTFields exposure time and there was increased R-loop formation. Furthermore, as cells were exposed to TTFields a conditional vulnerability environment developed which rendered cells more susceptible to DNA damaging agents or agents that interfere with DNA repair or replication fork maintenance. The effect of TTFields exposure with concomitant exposure to cisplatin or PARP inhibition, the combination of TTFields plus concomitant PARP inhibition followed by radiation, or radiation alone at the end of a TTFields exposure were all synergistic. Finally, gene expression analysis of 47 key mitosis regulator genes suggested that TTFields-induced mitotic aberrations and DNA damage/replication stress events, although intimately linked to one another, are likely initiated independently of one another. This suggests that enhanced replication stress and reduced DNA repair capacity are also major mechanisms of TTFields effects, effects for which there are therapeutic implications.
MeSH term(s)	Cell Line, Tumor ; Cisplatin/pharmacology ; DNA Damage ; DNA Replication ; Electric Stimulation Therapy/methods ; Humans ; Neoplasms/genetics ; Neoplasms/therapy ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Poly(ADP-ribose) Polymerases
Chemical Substances	Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases (EC 2.4.2.30) ; Cisplatin (Q20Q21Q62J)
Language	English
Publishing date	2019-10-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2246684-8
ISSN	1878-1810 ; 1532-6543 ; 1931-5244
ISSN (online)	1878-1810 ; 1532-6543
ISSN	1931-5244
DOI	10.1016/j.trsl.2019.10.003
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Article ; Online: Werner Syndrome Protein and DNA Replication

Shibani Mukherjee / Debapriya Sinha / Souparno Bhattacharya / Kalayarasan Srinivasan / Salim Abdisalaam / Aroumougame Asaithamby

International Journal of Molecular Sciences, Vol 19, Iss 11, p

2018 Volume 3442

Abstract: Werner Syndrome (WS) is an autosomal recessive disorder characterized by the premature development of aging features. Individuals with WS also have a greater predisposition to rare cancers that are mesenchymal in origin. Werner Syndrome Protein (WRN), ... ...

Abstract	Werner Syndrome (WS) is an autosomal recessive disorder characterized by the premature development of aging features. Individuals with WS also have a greater predisposition to rare cancers that are mesenchymal in origin. Werner Syndrome Protein (WRN), the protein mutated in WS, is unique among RecQ family proteins in that it possesses exonuclease and 3′ to 5′ helicase activities. WRN forms dynamic sub-complexes with different factors involved in DNA replication, recombination and repair. WRN binding partners either facilitate its DNA metabolic activities or utilize it to execute their specific functions. Furthermore, WRN is phosphorylated by multiple kinases, including Ataxia telangiectasia mutated, Ataxia telangiectasia and Rad3 related, c-Abl, Cyclin-dependent kinase 1 and DNA-dependent protein kinase catalytic subunit, in response to genotoxic stress. These post-translational modifications are critical for WRN to function properly in DNA repair, replication and recombination. Accumulating evidence suggests that WRN plays a crucial role in one or more genome stability maintenance pathways, through which it suppresses cancer and premature aging. Among its many functions, WRN helps in replication fork progression, facilitates the repair of stalled replication forks and DNA double-strand breaks associated with replication forks, and blocks nuclease-mediated excessive processing of replication forks. In this review, we specifically focus on human WRN’s contribution to replication fork processing for maintaining genome stability and suppressing premature aging. Understanding WRN’s molecular role in timely and faithful DNA replication will further advance our understanding of the pathophysiology of WS.
Keywords	cancer ; DNA double-strand repair ; premature aging ; post-translational modification ; protein stability ; replication stress ; Werner Syndrome ; Werner Syndrome Protein ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	612 ; 570
Language	English
Publishing date	2018-11-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: PTIP associates with Artemis to dictate DNA repair pathway choice.

Wang, Jiadong / Aroumougame, Asaithamby / Lobrich, Markus / Li, Yujing / Chen, David / Chen, Junjie / Gong, Zihua

Genes & development

2014 Volume 28, Issue 24, Page(s) 2693–2698

Abstract: PARP inhibitors (PARPis) are being used in patients with BRCA1/2 mutations. However, doubly deficient BRCA1(-/-)53BP1(-/-) cells or tumors become resistant to PARPis. Since 53BP1 or its known downstream effectors, PTIP and RIF1 (RAP1-interacting factor 1 ...

Abstract	PARP inhibitors (PARPis) are being used in patients with BRCA1/2 mutations. However, doubly deficient BRCA1(-/-)53BP1(-/-) cells or tumors become resistant to PARPis. Since 53BP1 or its known downstream effectors, PTIP and RIF1 (RAP1-interacting factor 1 homolog), lack enzymatic activities directly implicated in DNA repair, we decided to further explore the 53BP1-dependent pathway. In this study, we uncovered a nuclease, Artemis, as a PTIP-binding protein. Loss of Artemis restores PARPi resistance in BRCA1-deficient cells. Collectively, our data demonstrate that Artemis is the major downstream effector of the 53BP1 pathway, which prevents end resection and promotes nonhomologous end-joining and therefore directly competes with the homologous recombination repair pathway.
MeSH term(s)	Carrier Proteins/genetics ; Carrier Proteins/metabolism ; DNA Repair/genetics ; DNA Repair/physiology ; Endonucleases ; Gene Knockout Techniques ; HEK293 Cells ; HeLa Cells ; Humans ; Intracellular Signaling Peptides and Proteins/genetics ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Tumor Suppressor p53-Binding Protein 1
Chemical Substances	Carrier Proteins ; Intracellular Signaling Peptides and Proteins ; Nuclear Proteins ; PAXIP1 protein, human ; TP53BP1 protein, human ; Tumor Suppressor p53-Binding Protein 1 ; DCLRE1C protein, human (EC 3.1.-) ; Endonucleases (EC 3.1.-)
Language	English
Publishing date	2014-12-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	806684-x
ISSN	1549-5477 ; 0890-9369
ISSN (online)	1549-5477
ISSN	0890-9369
DOI	10.1101/gad.252478.114
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Zs.A 2292: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Nonenzymatic Role for WRN in Preserving Nascent DNA Strands after Replication Stress

Fengtao Su / Shibani Mukherjee / Yanyong Yang / Eiichiro Mori / Souparno Bhattacharya / Junya Kobayashi / Steven M. Yannone / David J. Chen / Aroumougame Asaithamby

Cell Reports, Vol 9, Iss 4, Pp 1387-

2014 Volume 1401

Abstract: WRN, the protein defective in Werner syndrome (WS), is a multifunctional nuclease involved in DNA damage repair, replication, and genome stability maintenance. It was assumed that the nuclease activities of WRN were critical for these functions. Here, we ...

Abstract	WRN, the protein defective in Werner syndrome (WS), is a multifunctional nuclease involved in DNA damage repair, replication, and genome stability maintenance. It was assumed that the nuclease activities of WRN were critical for these functions. Here, we report a nonenzymatic role for WRN in preserving nascent DNA strands following replication stress. We found that lack of WRN led to shortening of nascent DNA strands after replication stress. Furthermore, we discovered that the exonuclease activity of MRE11 was responsible for the shortening of newly replicated DNA in the absence of WRN. Mechanistically, the N-terminal FHA domain of NBS1 recruits WRN to replication-associated DNA double-stranded breaks to stabilize Rad51 and to limit the nuclease activity of its C-terminal binding partner MRE11. Thus, this previously unrecognized nonenzymatic function of WRN in the stabilization of nascent DNA strands sheds light on the molecular reason for the origin of genome instability in WS individuals.
Keywords	Biology (General) ; QH301-705.5
Subject code	612
Language	English
Publishing date	2014-11-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
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Article ; Online: Dynamin impacts homology-directed repair and breast cancer response to chemotherapy.

Chernikova, Sophia B / Nguyen, Rochelle B / Truong, Jessica T / Mello, Stephano S / Stafford, Jason H / Hay, Michael P / Olson, Andrew / Solow-Cordero, David E / Wood, Douglas J / Henry, Solomon / von Eyben, Rie / Deng, Lei / Gephart, Melanie Hayden / Aroumougame, Asaithamby / Wiese, Claudia / Game, John C / Győrffy, Balázs / Brown, J Martin

The Journal of clinical investigation

2018 Volume 128, Issue 12, Page(s) 5307–5321

Abstract: After the initial responsiveness of triple-negative breast cancers (TNBCs) to chemotherapy, they often recur as chemotherapy-resistant tumors, and this has been associated with upregulated homology-directed repair (HDR). Thus, inhibitors of HDR could be ... ...

Abstract	After the initial responsiveness of triple-negative breast cancers (TNBCs) to chemotherapy, they often recur as chemotherapy-resistant tumors, and this has been associated with upregulated homology-directed repair (HDR). Thus, inhibitors of HDR could be a useful adjunct to chemotherapy treatment of these cancers. We performed a high-throughput chemical screen for inhibitors of HDR from which we obtained a number of hits that disrupted microtubule dynamics. We postulated that high levels of the target molecules of our screen in tumors would correlate with poor chemotherapy response. We found that inhibition or knockdown of dynamin 2 (DNM2), known for its role in endocytic cell trafficking and microtubule dynamics, impaired HDR and improved response to chemotherapy of cells and of tumors in mice. In a retrospective analysis, levels of DNM2 at the time of treatment strongly predicted chemotherapy outcome for estrogen receptor-negative and especially for TNBC patients. We propose that DNM2-associated DNA repair enzyme trafficking is important for HDR efficiency and is a powerful predictor of sensitivity to breast cancer chemotherapy and an important target for therapy.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; CHO Cells ; Cricetulus ; Dynamin II ; Dynamins/genetics ; Dynamins/metabolism ; Female ; Humans ; Mice ; Mice, Nude ; Recombinational DNA Repair ; Triple Negative Breast Neoplasms/drug therapy ; Triple Negative Breast Neoplasms/enzymology ; Triple Negative Breast Neoplasms/genetics ; Triple Negative Breast Neoplasms/pathology ; Xenograft Model Antitumor Assays
Chemical Substances	Antineoplastic Agents ; DNM2 protein, human (EC 3.6.5.5) ; Dynamin II (EC 3.6.5.5) ; Dynamins (EC 3.6.5.5)
Language	English
Publishing date	2018-10-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI87191
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Article ; Online: MOF Phosphorylation by ATM Regulates 53BP1-Mediated Double-Strand Break Repair Pathway Choice

Arun Gupta / Clayton R. Hunt / Muralidhar L. Hegde / Sharmistha Chakraborty / Durga Udayakumar / Nobuo Horikoshi / Mayank Singh / Deepti B. Ramnarain / Walter N. Hittelman / Sarita Namjoshi / Aroumougame Asaithamby / Tapas K. Hazra / Thomas Ludwig / Raj K. Pandita / Jessica K. Tyler / Tej K. Pandita

Cell Reports, Vol 8, Iss 1, p

2014 Volume 319

Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2014-07-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: MOF Phosphorylation by ATM Regulates 53BP1-Mediated Double-Strand Break Repair Pathway Choice

Cell Reports, Vol 8, Iss 1, Pp 177-

2014 Volume 189

Abstract: Cell-cycle phase is a critical determinant of the choice between DNA damage repair by nonhomologous end-joining (NHEJ) or homologous recombination (HR). Here, we report that double-strand breaks (DSBs) induce ATM-dependent MOF (a histone H4 acetyl- ... ...

Abstract	Cell-cycle phase is a critical determinant of the choice between DNA damage repair by nonhomologous end-joining (NHEJ) or homologous recombination (HR). Here, we report that double-strand breaks (DSBs) induce ATM-dependent MOF (a histone H4 acetyl-transferase) phosphorylation (p-T392-MOF) and that phosphorylated MOF colocalizes with γ-H2AX, ATM, and 53BP1 foci. Mutation of the phosphorylation site (MOF-T392A) impedes DNA repair in S and G2 phase but not G1 phase cells. Expression of MOF-T392A also blocks the reduction in DSB-associated 53BP1 seen in wild-type S/G2 phase cells, resulting in enhanced 53BP1 and reduced BRCA1 association. Decreased BRCA1 levels at DSB sites correlates with defective repairosome formation, reduced HR repair, and decreased cell survival following irradiation. These data support a model whereby ATM-mediated MOF-T392 phosphorylation modulates 53BP1 function to facilitate the subsequent recruitment of HR repair proteins, uncovering a regulatory role for MOF in DSB repair pathway choice during S/G2 phase.
Keywords	Biology (General) ; QH301-705.5
Subject code	612
Language	English
Publishing date	2014-07-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The oxygen-rich postnatal environment induces cardiomyocyte cell-cycle arrest through DNA damage response.

Puente, Bao N / Kimura, Wataru / Muralidhar, Shalini A / Moon, Jesung / Amatruda, James F / Phelps, Kate L / Grinsfelder, David / Rothermel, Beverly A / Chen, Rui / Garcia, Joseph A / Santos, Celio X / Thet, SuWannee / Mori, Eiichiro / Kinter, Michael T / Rindler, Paul M / Zacchigna, Serena / Mukherjee, Shibani / Chen, David J / Mahmoud, Ahmed I /

Giacca, Mauro / Rabinovitch, Peter S / Aroumougame, Asaithamby / Shah, Ajay M / Szweda, Luke I / Sadek, Hesham A

Cell

2014 Volume 157, Issue 3, Page(s) 565–579

Abstract: The mammalian heart has a remarkable regenerative capacity for a short period of time after birth, after which the majority of cardiomyocytes permanently exit cell cycle. We sought to determine the primary postnatal event that results in cardiomyocyte ... ...

Abstract	The mammalian heart has a remarkable regenerative capacity for a short period of time after birth, after which the majority of cardiomyocytes permanently exit cell cycle. We sought to determine the primary postnatal event that results in cardiomyocyte cell-cycle arrest. We hypothesized that transition to the oxygen-rich postnatal environment is the upstream signal that results in cell-cycle arrest of cardiomyocytes. Here, we show that reactive oxygen species (ROS), oxidative DNA damage, and DNA damage response (DDR) markers significantly increase in the heart during the first postnatal week. Intriguingly, postnatal hypoxemia, ROS scavenging, or inhibition of DDR all prolong the postnatal proliferative window of cardiomyocytes, whereas hyperoxemia and ROS generators shorten it. These findings uncover a protective mechanism that mediates cardiomyocyte cell-cycle arrest in exchange for utilization of oxygen-dependent aerobic metabolism. Reduction of mitochondrial-dependent oxidative stress should be an important component of cardiomyocyte proliferation-based therapeutic approaches.
MeSH term(s)	Acetylcysteine/pharmacology ; Animals ; Cell Cycle Checkpoints ; Cell Proliferation/drug effects ; DNA Damage ; Free Radical Scavengers/pharmacology ; Mice ; Mitochondria/metabolism ; Myocytes, Cardiac/cytology ; Myocytes, Cardiac/metabolism ; Reactive Oxygen Species/metabolism ; Zebrafish
Chemical Substances	Free Radical Scavengers ; Reactive Oxygen Species ; Acetylcysteine (WYQ7N0BPYC)
Language	English
Publishing date	2014-04-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2014.03.032
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Zs.A 1167: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 58: Show issues

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