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Article: Editorial: Defective DNA damage response-Repair axis in post-mitotic neurons in human health and neurodegenerative diseases.

Konopka, Anna / Atkin, Julie D / Mitra, Joy

2022 Volume 16, Page(s) 1009760

Language	English
Publishing date	2022-08-23
Publishing country	Switzerland
Document type	Editorial
ZDB-ID	2452963-1
ISSN	1662-5102
ISSN	1662-5102
DOI	10.3389/fncel.2022.1009760
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Article ; Online: DNA Double-Strand Breaks as Pathogenic Lesions in Neurological Disorders.

Provasek, Vincent E / Mitra, Joy / Malojirao, Vikas H / Hegde, Muralidhar L

International journal of molecular sciences

2022 Volume 23, Issue 9

Abstract: The damage and repair of DNA is a continuous process required to maintain genomic integrity. DNA double-strand breaks (DSBs) are the most lethal type of DNA damage and require timely repair by dedicated machinery. DSB repair is uniquely important to ... ...

Abstract	The damage and repair of DNA is a continuous process required to maintain genomic integrity. DNA double-strand breaks (DSBs) are the most lethal type of DNA damage and require timely repair by dedicated machinery. DSB repair is uniquely important to nondividing, post-mitotic cells of the central nervous system (CNS). These long-lived cells must rely on the intact genome for a lifetime while maintaining high metabolic activity. When these mechanisms fail, the loss of certain neuronal populations upset delicate neural networks required for higher cognition and disrupt vital motor functions. Mammalian cells engage with several different strategies to recognize and repair chromosomal DSBs based on the cellular context and cell cycle phase, including homologous recombination (HR)/homology-directed repair (HDR), microhomology-mediated end-joining (MMEJ), and the classic non-homologous end-joining (NHEJ). In addition to these repair pathways, a growing body of evidence has emphasized the importance of DNA damage response (DDR) signaling, and the involvement of heterogeneous nuclear ribonucleoprotein (hnRNP) family proteins in the repair of neuronal DSBs, many of which are linked to age-associated neurological disorders. In this review, we describe contemporary research characterizing the mechanistic roles of these non-canonical proteins in neuronal DSB repair, as well as their contributions to the etiopathogenesis of selected common neurological diseases.
MeSH term(s)	Animals ; DNA/genetics ; DNA Breaks, Double-Stranded ; DNA End-Joining Repair ; DNA Repair ; Mammals/genetics ; Nervous System Diseases/genetics ; Recombinational DNA Repair
Chemical Substances	DNA (9007-49-2)
Language	English
Publishing date	2022-04-22
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23094653
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Article: A Commentary on TDP-43 and DNA Damage Response in Amyotrophic Lateral Sclerosis.

Mitra, Joy / Hegde, Muralidhar L

Journal of experimental neuroscience

2019 Volume 13, Page(s) 1179069519880166

Abstract: Amyotrophic lateral sclerosis (ALS) is a devastating, motor neuron degenerative disease without any cure. About 95% of the ALS patients feature abnormalities in the RNA/DNA-binding protein, TDP-43, involving its nucleo-cytoplasmic mislocalization in ... ...

Abstract	Amyotrophic lateral sclerosis (ALS) is a devastating, motor neuron degenerative disease without any cure. About 95% of the ALS patients feature abnormalities in the RNA/DNA-binding protein, TDP-43, involving its nucleo-cytoplasmic mislocalization in spinal motor neurons. How TDP-43 pathology triggers neuronal apoptosis remains unclear. In a recent study, we reported for the first time that TDP-43 participates in the DNA damage response (DDR) in neurons, and its nuclear clearance in spinal motor neurons caused DNA double-strand break (DSB) repair defects in ALS. We documented that TDP-43 was a key component of the non-homologous end joining (NHEJ) pathway of DSB repair, which is likely the major pathway for repair of DSBs in post-mitotic neurons. We have also uncovered molecular insights into the role of TDP-43 in DSB repair and showed that TDP-43 acts as a scaffold in recruiting the XRCC4/DNA Ligase 4 complex at DSB damage sites and thus regulates a critical rate-limiting function in DSB repair. Significant DSB accumulation in the genomes of TDP-43-depleted, human neural stem cell-derived motor neurons as well as in ALS patient spinal cords with TDP-43 pathology, strongly supported a TDP-43 involvement in genome maintenance and toxicity-induced genome repair defects in ALS. In this commentary, we highlight our findings that have uncovered a link between TDP-43 pathology and impaired DNA repair and suggest potential possibilities for DNA repair-targeted therapies for TDP-43-ALS.
Language	English
Publishing date	2019-10-10
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	2659991-0
ISSN	1179-0695
ISSN	1179-0695
DOI	10.1177/1179069519880166
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Article ; Online: Characterizing the Repair of DNA Double-Strand Breaks: A Review of Surrogate Plasmid-Based Reporter Methods.

Dutta, Arijit / Mitra, Joy / Hegde, Pavana M / Mitra, Sankar / Hegde, Muralidhar L

Methods in molecular biology (Clifton, N.J.)

2023 Volume 2701, Page(s) 173–182

Abstract: DNA double-strand breaks (DSBs) are the most lethal genomic lesions that are induced endogenously during physiological reactions as well as by external stimuli and genotoxicants. DSBs are repaired in mammalian cells via one of three well-studied pathways ...

Abstract	DNA double-strand breaks (DSBs) are the most lethal genomic lesions that are induced endogenously during physiological reactions as well as by external stimuli and genotoxicants. DSBs are repaired in mammalian cells via one of three well-studied pathways depending on the cell cycle status and/or the nature of the break. First, the homologous recombination (HR) pathway utilizes the duplicated sister chromatid as a template in S/G
MeSH term(s)	Animals ; Humans ; DNA Breaks, Double-Stranded ; Reactive Oxygen Species ; DNA End-Joining Repair ; DNA/metabolism ; Plasmids/genetics ; DNA Repair ; Mammals/metabolism
Chemical Substances	Reactive Oxygen Species ; DNA (9007-49-2)
Language	English
Publishing date	2023-07-28
Publishing country	United States
Document type	Review ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-3373-1_11
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Article ; Online: Mobility Enhancement in CVD-Grown Monolayer MoS

Kayal, Arijit / Dey, Sraboni / G, Harikrishnan / Nadarajan, Renjith / Chattopadhyay, Shashwata / Mitra, Joy

Nano letters

2023 Volume 23, Issue 14, Page(s) 6629–6636

Abstract: The extraordinary mechanical properties of two-dimensional transition-metal dichalcogenides make them ideal candidates for investigating strain-induced control of various physical properties. Here we explore the role of nonuniform strain in modulating ... ...

Abstract	The extraordinary mechanical properties of two-dimensional transition-metal dichalcogenides make them ideal candidates for investigating strain-induced control of various physical properties. Here we explore the role of nonuniform strain in modulating optical, electronic, and transport properties of semiconducting, chemical vapor deposited monolayer MoS
Language	English
Publishing date	2023-06-22
Publishing country	United States
Document type	Journal Article
ISSN	1530-6992
ISSN (online)	1530-6992
DOI	10.1021/acs.nanolett.3c01774
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Article: Mitochondria-Targeted Oligomeric α-Synuclein Induces TOM40 Degradation and Mitochondrial Dysfunction in Parkinson's Disease and Parkinsonism-Dementia of Guam.

Hegde, Muralidhar / Vasquez, Velmarini / Kodavati, Manohar / Mitra, Joy / Vendula, Indira / Hamilton, Dale / Garruto, Ralph / Rao, K S

Research square

2024

Abstract: Mitochondrial dysfunction is a central aspect of Parkinson's disease (PD) pathology, yet the underlying mechanisms are not fully understood. This study investigates the link between α-Synuclein (α-Syn) pathology and the loss of translocase of the outer ... ...

Abstract	Mitochondrial dysfunction is a central aspect of Parkinson's disease (PD) pathology, yet the underlying mechanisms are not fully understood. This study investigates the link between α-Synuclein (α-Syn) pathology and the loss of translocase of the outer mitochondrial membrane 40 (TOM40), unraveling its implications for mitochondrial dysfunctions in neurons. We discovered that TOM40 protein depletion occurs in the brains of patients with Guam Parkinsonism Dementia (Guam PD) and cultured neurons expressing α-Syn proteinopathy, notably, without corresponding changes in TOM40 mRNA levels. Cultured neurons expressing α-Syn mutants, with or without a mitochondria-targeting signal (MTS) underscore the role of α-Syn's mitochondrial localization in inducing TOM40 degradation. Parkinson's Disease related etiological factors, such as 6-hydroxy dopamine or ROS/metal ions stress, which promote α-Syn oligomerization, exacerbate TOM40 depletion in PD patient-derived cells with SNCA gene triplication. Although α-Syn interacts with both TOM40 and TOM20 in the outer mitochondrial membrane, degradation is selective for TOM40, which occurs via the ubiquitin-proteasome system (UPS) pathway. Our comprehensive analyses using Seahorse technology, mitochondrial DNA sequencing, and damage assessments, demonstrate that mutant α-Syn-induced TOM40 loss results in mitochondrial dysfunction, characterized by reduced membrane potential, accumulation of mtDNA damage, deletion/insertion mutations, and altered oxygen consumption rates. Notably, ectopic supplementation of TOM40 or reducing pathological forms of α-Syn using ADP-ribosylation inhibitors ameliorate these mitochondrial defects, suggesting potential therapeutic avenues. In conclusion, our findings provide crucial mechanistic insights into how α-Syn accumulation leads to TOM40 degradation and mitochondrial dysfunction, offering insights for targeted interventions to alleviate mitochondrial defects in PD.
Language	English
Publishing date	2024-02-21
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3970470/v1
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Article: Endogenous TDP-43 mislocalization in a novel knock-in mouse model reveals DNA repair impairment, inflammation, and neuronal senescence.

Mitra, Joy / Dharmalingam, Prakash / Kodavati, Manohar / Guerrero, Erika N / Rao, K S / Garruto, Ralph M / Hegde, Muralidhar L

Research square

2024

Abstract: TDP-43 mislocalization and aggregation are key pathological features of motor neuron diseases (MND) including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, transgenic hTDP-43 WT or ΔNLS-overexpression animal models ... ...

Abstract	TDP-43 mislocalization and aggregation are key pathological features of motor neuron diseases (MND) including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, transgenic hTDP-43 WT or ΔNLS-overexpression animal models mainly capture late-stages TDP-43 proteinopathy, and do not provide a complete understanding of early motor neuron-specific pathology during pre-symptomatic phases. We have now addressed this shortcoming by generating a new endogenous knock-in (KI) mouse model using a combination of CRISPR/Cas9 and FLEX Cre-switch strategy for the conditional expression of a mislocalized Tdp-43ΔNLS variant of mouse Tdp-43. This variant is either expressed conditionally in whole mice or specifically in the motor neurons. The mice exhibit loss of nuclear Tdp-43 concomitant with its cytosolic accumulation and aggregation in targeted cells, leading to increased DNA double-strand breaks (DSBs), signs of inflammation and DNA damage-associated cellular senescence. Notably, unlike WT Tdp43 which functionally interacts with Xrcc4 and DNA Ligase 4, the key DSB repair proteins in the non-homologous end-joining (NHEJ) pathway, the Tdp-43ΔNLS mutant sequesters them into cytosolic aggregates, exacerbating neuronal damage in mice brain. The mutant mice also exhibit myogenic degeneration in limb muscles and distinct motor deficits, consistent with the characteristics of MND. Our findings reveal progressive degenerative mechanisms in motor neurons expressing endogenous Tdp-43ΔNLS mutant, independent of TDP-43 overexpression or other confounding etiological factors. Thus, this unique Tdp-43 KI mouse model, which displays key molecular and phenotypic features of Tdp-43 proteinopathy, offers a significant opportunity to further characterize the early-stage progression of MND and also opens avenues for developing DNA repair-targeted approaches for treating TDP-43 pathology-linked neurodegenerative diseases.
Language	English
Publishing date	2024-03-20
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3879966/v2
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Article ; Online: Enhancement of Photoacoustic Signal Strength with Continuous Wave Optical Pre-Illumination: A Non-Invasive Technique.

Thomas, Anjali / Paul, Souradip / Mitra, Joy / Singh, Mayanglambam Suheshkumar

Sensors (Basel, Switzerland)

2021 Volume 21, Issue 4

Abstract: Use of portable and affordable pulse light sources (light emitting diodes (LED) and laser diodes) for tissue illumination offers an opportunity to accelerate the clinical translation of photoacoustic imaging (PAI) technology. However, imaging depth in ... ...

Abstract	Use of portable and affordable pulse light sources (light emitting diodes (LED) and laser diodes) for tissue illumination offers an opportunity to accelerate the clinical translation of photoacoustic imaging (PAI) technology. However, imaging depth in this case is limited because of low output (optical) power of these light sources. In this work, we developed a noninvasive technique for enhancing strength (amplitude) of photoacoustic (PA) signal. This is a photothermal-based technique in which a continuous wave (CW) optical beam, in addition to short-pulse ~ nsec laser beam, is employed to irradiate and, thus, raise the temperature of sample material selectively over a pre-specified region of interest (we call the process as pre-illumination). The increase in temperature, in turn enhances the PA-signal strength. Experiments were conducted in methylene blue, which is one of the commonly used contrast agents in laboratory research studies, to validate change in temperature and subsequent enhancement of PA-signal strength for the following cases: (1) concentration or optical absorption coefficient of sample, (2) optical power of CW-optical beam, and (3) time duration of pre-illumination. A theoretical hypothesis, being validated by numerical simulation, is presented. To validate the proposed technique for clinical and/or pre-clinical applications (diagnosis and treatments of cancer, pressure ulcers, and minimally invasive procedures including vascular access and fetal surgery), experiments were conducted in tissue-mimicking Agar phantom and ex-vivo animal tissue (chicken breast). Results demonstrate that pre-illumination significantly enhances PA-signal strength (up to ~70% (methylene blue), ~48% (Agar phantom), and ~40% (chicken tissue)). The proposed technique addresses one of the primary challenges in the clinical translation of LED-based PAI systems (more specifically, to obtain a detectable PA-signal from deep-seated tissue targets).
Language	English
Publishing date	2021-02-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2052857-7
ISSN	1424-8220 ; 1424-8220
ISSN (online)	1424-8220
ISSN	1424-8220
DOI	10.3390/s21041190
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Article ; Online: Two-Dimensional Silver-Chalcogenolate-Based Cluster-Assembled Material: A

Das, Anish Kumar / Biswas, Sourav / Kayal, Arijit / Reber, Arthur C / Bhandary, Subhrajyoti / Chopra, Deepak / Mitra, Joy / Khanna, Shiv N / Mandal, Sukhendu

Nano letters

2023 Volume 23, Issue 19, Page(s) 8923–8931

Abstract: We have synthesized and characterized a new two-dimensional honeycomb architecture resembling a single-layer of atomically precise silver cluster-assembled material (CAM), [ ... ...

Abstract	We have synthesized and characterized a new two-dimensional honeycomb architecture resembling a single-layer of atomically precise silver cluster-assembled material (CAM), [Ag
Language	English
Publishing date	2023-09-19
Publishing country	United States
Document type	Journal Article
ISSN	1530-6992
ISSN (online)	1530-6992
DOI	10.1021/acs.nanolett.3c02269
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Article ; Online: Human DNA polymerase η promotes RNA-templated error-free repair of DNA double-strand breaks.

Chakraborty, Anirban / Tapryal, Nisha / Islam, Azharul / Sarker, Altaf H / Manohar, Kodavati / Mitra, Joy / Hegde, Muralidhar L / Hazra, Tapas

The Journal of biological chemistry

2023 Volume 299, Issue 3, Page(s) 102991

Abstract: A growing body of evidence indicates that RNA plays a critical role in orchestrating DNA double-strand break repair (DSBR). Recently, we showed that homologous nascent RNA can be used as a template for error-free repair of double-strand breaks (DSBs) in ... ...

Abstract	A growing body of evidence indicates that RNA plays a critical role in orchestrating DNA double-strand break repair (DSBR). Recently, we showed that homologous nascent RNA can be used as a template for error-free repair of double-strand breaks (DSBs) in the transcribed genome and to restore the missing sequence at the break site via the transcription-coupled classical nonhomologous end-joining (TC-NHEJ) pathway. TC-NHEJ is a complex multistep process in which a reverse transcriptase (RT) is essential for synthesizing the DNA strand from template RNA. However, the identity of the RT involved in the TC-NHEJ pathway remained unknown. Here, we report that DNA polymerase eta (Pol η), known to possess RT activity, plays a critical role in TC-NHEJ. We found that Pol η forms a multiprotein complex with RNAP II and other TC-NHEJ factors, while also associating with nascent RNA. Moreover, purified Pol η, along with DSBR proteins PNKP, XRCC4, and Ligase IV can fully repair RNA templated 3'-phosphate-containing gapped DNA substrate. In addition, we demonstrate here that Pol η deficiency leads to accumulation of R-loops and persistent strand breaks in the transcribed genes. Finally, we determined that, in Pol η depleted but not in control cells, TC-NHEJ-mediated repair was severely abrogated when a reporter plasmid containing a DSB with several nucleotide deletion within the E. coli lacZ gene was introduced for repair in lacZ-expressing mammalian cells. Thus, our data strongly suggest that RT activity of Pol η is required in error-free DSBR.
MeSH term(s)	Animals ; Humans ; DNA Breaks, Double-Stranded ; Escherichia coli/genetics ; DNA Repair ; DNA End-Joining Repair ; DNA ; RNA/genetics ; DNA Ligase ATP ; Mammals ; Phosphotransferases (Alcohol Group Acceptor)/genetics ; DNA Repair Enzymes/genetics
Chemical Substances	Rad30 protein (EC 2.7.7.7) ; DNA (9007-49-2) ; RNA (63231-63-0) ; DNA Ligase ATP (EC 6.5.1.1) ; PNKP protein, human (EC 2.7.1.-) ; Phosphotransferases (Alcohol Group Acceptor) (EC 2.7.1.-) ; DNA Repair Enzymes (EC 6.5.1.-)
Language	English
Publishing date	2023-02-08
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2023.102991
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