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  1. Article: Exploring role of 5hmC as potential marker of chemoresistance.

    Kharat, Suhas S / Sharan, Shyam K

    Molecular & cellular oncology

    2020  Volume 7, Issue 6, Page(s) 1827904

    Abstract: Chemoresistance remains to be a common and significant hurdle with all chemotherapies. Tumors gain resistance by acquiring additional mutations. Some of the chemoresistance mechanisms are known and can be tackled. However, the majority of chemoresistance ...

    Abstract Chemoresistance remains to be a common and significant hurdle with all chemotherapies. Tumors gain resistance by acquiring additional mutations. Some of the chemoresistance mechanisms are known and can be tackled. However, the majority of chemoresistance mechanisms are unknown. Our recent findings shed light on one such unknown mechanism. We identified a novel role for 5-hydroxymethycytosine (5hmC), an epigenetic mark on the DNA, in maintaining the integrity of stalled replication forks and its impact on genomic stability and chemoresistance.
    Language English
    Publishing date 2020-10-22
    Publishing country United States
    Document type Journal Article
    ISSN 2372-3556
    ISSN 2372-3556
    DOI 10.1080/23723556.2020.1827904
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: XPA tumor variant leads to defects in NER that sensitize cells to cisplatin.

    Blee, Alexandra M / Gallagher, Kaitlyn S / Kim, Hyun-Suk / Kim, Mihyun / Kharat, Suhas S / Troll, Christina R / D'Souza, Areetha / Park, Jiyoung / Neufer, P Drew / Schärer, Orlando D / Chazin, Walter J

    NAR cancer

    2024  Volume 6, Issue 1, Page(s) zcae013

    Abstract: Nucleotide excision repair (NER) reduces efficacy of treatment with platinum (Pt)-based chemotherapy by removing Pt lesions from DNA. Previous study has identified that missense mutation or loss of the NER genes Excision Repair Cross Complementation ... ...

    Abstract Nucleotide excision repair (NER) reduces efficacy of treatment with platinum (Pt)-based chemotherapy by removing Pt lesions from DNA. Previous study has identified that missense mutation or loss of the NER genes Excision Repair Cross Complementation Group 1 and 2 (
    Language English
    Publishing date 2024-03-18
    Publishing country England
    Document type Journal Article
    ISSN 2632-8674
    ISSN (online) 2632-8674
    DOI 10.1093/narcan/zcae013
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Mismatch repair protein MLH1 suppresses replicative stress in BRCA2-deficient breast tumors.

    Sengodan, Satheesh K / Hu, Xiaoju / Peddibhotla, Vaishnavi / Balamurugan, Kuppusamy / Mitrophanov, Alexander Y / McKennett, Lois / Kharat, Suhas S / Sanawar, Rahul / Singh, Vinod Kumar / Albaugh, Mary E / Burkett, Sandra S / Zhao, Yongmei / Tran, Bao / Malys, Tyler / Sterneck, Esta / De, Subhajyoti / Sharan, Shyam K

    The Journal of clinical investigation

    2024  Volume 134, Issue 7

    Abstract: Loss of BRCA2 (breast cancer 2) is lethal for normal cells. Yet it remains poorly understood how, in BRCA2 mutation carriers, cells undergoing loss of heterozygosity overcome the lethality and undergo tissue-specific neoplastic transformation. Here, we ... ...

    Abstract Loss of BRCA2 (breast cancer 2) is lethal for normal cells. Yet it remains poorly understood how, in BRCA2 mutation carriers, cells undergoing loss of heterozygosity overcome the lethality and undergo tissue-specific neoplastic transformation. Here, we identified mismatch repair gene mutL homolog 1 (MLH1) as a genetic interactor of BRCA2 whose overexpression supports the viability of Brca2-null cells. Mechanistically, we showed that MLH1 interacts with Flap endonuclease 1 (FEN1) and competes to process the RNA flaps of Okazaki fragments. Together, they restrained the DNA2 nuclease activity on the reversed forks of lagging strands, leading to replication fork (RF) stability in BRCA2-deficient cells. In these cells, MLH1 also attenuated R-loops, allowing the progression of stable RFs, which suppressed genomic instability and supported cell viability. We demonstrated the significance of their genetic interaction by the lethality of Brca2-mutant mice and inhibition of Brca2-deficient tumor growth in mice by Mlh1 loss. Furthermore, we described estrogen as inducing MLH1 expression through estrogen receptor α (ERα), which might explain why the majority of BRCA2 mutation carriers develop ER-positive breast cancer. Taken together, our findings reveal a role of MLH1 in relieving replicative stress and show how it may contribute to the establishment of BRCA2-deficient breast tumors.
    MeSH term(s) Animals ; Mice ; BRCA2 Protein/genetics ; BRCA2 Protein/metabolism ; MutL Protein Homolog 1/genetics ; MutL Protein Homolog 1/metabolism ; DNA Mismatch Repair ; DNA Replication ; Mammary Neoplasms, Animal
    Chemical Substances BRCA2 Protein ; MutL Protein Homolog 1 (EC 3.6.1.3)
    Language English
    Publishing date 2024-01-25
    Publishing country United States
    Document type Journal Article
    ZDB-ID 3067-3
    ISSN 1558-8238 ; 0021-9738
    ISSN (online) 1558-8238
    ISSN 0021-9738
    DOI 10.1172/JCI173718
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Interferon restores replication fork stability and cell viability in BRCA-defective cells via ISG15.

    Moro, Ramona N / Biswas, Uddipta / Kharat, Suhas S / Duzanic, Filip D / Das, Prosun / Stavrou, Maria / Raso, Maria C / Freire, Raimundo / Chaudhuri, Arnab Ray / Sharan, Shyam K / Penengo, Lorenza

    Nature communications

    2023  Volume 14, Issue 1, Page(s) 6140

    Abstract: DNA replication and repair defects or genotoxic treatments trigger interferon (IFN)-mediated inflammatory responses. However, whether and how IFN signaling in turn impacts the DNA replication process has remained elusive. Here we show that basal levels ... ...

    Abstract DNA replication and repair defects or genotoxic treatments trigger interferon (IFN)-mediated inflammatory responses. However, whether and how IFN signaling in turn impacts the DNA replication process has remained elusive. Here we show that basal levels of the IFN-stimulated gene 15, ISG15, and its conjugation (ISGylation) are essential to protect nascent DNA from degradation. Moreover, IFNβ treatment restores replication fork stability in BRCA1/2-deficient cells, which strictly depends on topoisomerase-1, and rescues lethality of BRCA2-deficient mouse embryonic stem cells. Although IFNβ activates hundreds of genes, these effects are specifically mediated by ISG15 and ISGylation, as their inactivation suppresses the impact of IFNβ on DNA replication. ISG15 depletion significantly reduces cell proliferation rates in human BRCA1-mutated triple-negative, whereas its upregulation results in increased resistance to the chemotherapeutic drug cisplatin in mouse BRCA2-deficient breast cancer cells, respectively. Accordingly, cells carrying BRCA1/2 defects consistently show increased ISG15 levels, which we propose as an in-built mechanism of drug resistance linked to BRCAness.
    MeSH term(s) Animals ; Humans ; Mice ; Interferons ; BRCA1 Protein/genetics ; Cell Survival ; BRCA2 Protein/metabolism ; Ubiquitins/genetics ; Ubiquitins/metabolism ; Cytokines/metabolism
    Chemical Substances Interferons (9008-11-1) ; BRCA1 protein, human ; BRCA1 Protein ; BRCA2 protein, human ; BRCA2 Protein ; Ubiquitins ; Cytokines ; ISG15 protein, human (60267-61-0)
    Language English
    Publishing date 2023-10-02
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-023-41801-w
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Characterization of BRCA2 R3052Q variant in mice supports its functional impact as a low-risk variant.

    Mishra, Arun Prakash / Hartford, Suzanne / Chittela, Rajani Kant / Sahu, Sounak / Kharat, Suhas S / Alvaro-Aranda, Lucia / Contreras-Perez, Aida / Sullivan, Teresa / Martin, Betty K / Albaugh, Mary / Southon, Eileen / Burkett, Sandra / Karim, Baktiar / Carreira, Aura / Tessarollo, Lino / Sharan, Shyam K

    Cell death & disease

    2023  Volume 14, Issue 11, Page(s) 753

    Abstract: Pathogenic variants in BRCA2 are known to significantly increase the lifetime risk of developing breast and ovarian cancers. Sequencing-based genetic testing has resulted in the identification of thousands of BRCA2 variants that are considered to be ... ...

    Abstract Pathogenic variants in BRCA2 are known to significantly increase the lifetime risk of developing breast and ovarian cancers. Sequencing-based genetic testing has resulted in the identification of thousands of BRCA2 variants that are considered to be variants of uncertain significance (VUS) because the disease risk associated with them is unknown. One such variant is p.Arg3052Gln, which has conflicting interpretations of pathogenicity in the ClinVar variant database. Arginine at position 3052 in BRCA2 plays an important role in stabilizing its C-terminal DNA binding domain. We have generated a knock-in mouse model expressing this variant to examine its role on growth and survival in vivo. Homozygous as well as hemizygous mutant mice are viable, fertile and exhibit no overt phenotype. While we did not observe any hematopoietic defects in adults, we did observe a marked reduction in the in vitro proliferative ability of fetal liver cells that were also hypersensitive to PARP inhibitor, olaparib. In vitro studies performed on embryonic and adult fibroblasts derived from the mutant mice showed significant reduction in radiation induced RAD51 foci formation as well as increased genomic instability after mitomycin C treatment. We observed mis-localization of a fraction of R3052Q BRCA2 protein to the cytoplasm which may explain the observed in vitro phenotypes. Our findings suggest that BRCA2 R3052Q should be considered as a hypomorphic variant.
    MeSH term(s) Humans ; Female ; Mice ; Animals ; BRCA2 Protein/genetics ; BRCA2 Protein/metabolism ; Genetic Testing ; Antineoplastic Agents ; Ovarian Neoplasms/genetics ; Homozygote ; Breast Neoplasms/genetics ; BRCA1 Protein/genetics ; Genetic Predisposition to Disease
    Chemical Substances BRCA2 Protein ; Antineoplastic Agents ; BRCA1 Protein ; BRCA2 protein, human
    Language English
    Publishing date 2023-11-18
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Intramural
    ZDB-ID 2541626-1
    ISSN 2041-4889 ; 2041-4889
    ISSN (online) 2041-4889
    ISSN 2041-4889
    DOI 10.1038/s41419-023-06289-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Degradation of 5hmC-marked stalled replication forks by APE1 causes genomic instability.

    Kharat, Suhas S / Ding, Xia / Swaminathan, Divya / Suresh, Akshey / Singh, Manish / Sengodan, Satheesh K / Burkett, Sandra / Marks, Hanna / Pamala, Chinmayi / He, Yafeng / Fox, Stephen D / Buehler, Eugen C / Muegge, Kathrin / Martin, Scott E / Sharan, Shyam K

    Science signaling

    2020  Volume 13, Issue 645

    Abstract: Synthetic lethality between poly(ADP-ribose) polymerase (PARP) inhibition ... ...

    Abstract Synthetic lethality between poly(ADP-ribose) polymerase (PARP) inhibition and
    MeSH term(s) 5-Methylcytosine/metabolism ; Animals ; Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Cell Line ; Cell Line, Tumor ; DNA Replication/genetics ; DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics ; DNA-(Apurinic or Apyrimidinic Site) Lyase/metabolism ; Deoxycytidine/analogs & derivatives ; Deoxycytidine/metabolism ; Drug Resistance, Neoplasm/genetics ; Female ; Genomic Instability/genetics ; Humans ; Mice ; Mice, Nude ; Neoplasms, Experimental/drug therapy ; Neoplasms, Experimental/genetics ; Neoplasms, Experimental/metabolism ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/metabolism ; Phthalazines/pharmacology ; Piperazines/pharmacology ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology
    Chemical Substances 5-hydroxymethyl-2'-deoxycytidine ; Phthalazines ; Piperazines ; Poly(ADP-ribose) Polymerase Inhibitors ; Deoxycytidine (0W860991D6) ; 5-Methylcytosine (6R795CQT4H) ; APEX1 protein, human (EC 4.2.99.18) ; DNA-(Apurinic or Apyrimidinic Site) Lyase (EC 4.2.99.18) ; olaparib (WOH1JD9AR8)
    Language English
    Publishing date 2020-08-18
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Intramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2417226-1
    ISSN 1937-9145 ; 1945-0877
    ISSN (online) 1937-9145
    ISSN 1945-0877
    DOI 10.1126/scisignal.aba8091
    Database MEDical Literature Analysis and Retrieval System OnLINE

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