XAB2 promotes Ku eviction from single-ended DNA double-strand breaks independently of the ATM kinase

Sharma, Abhishek Bharadwaj; Erasimus, Hélène; Pinto, Lia; Caron, Marie-Christine; Gopaul, Diyavarshini; Peterlini, Thibaut; Neumann, Katrin; Nazarov, Petr V.; Fritah, Sabrina; Klink, Barbara; Herold‐Mende, Christel; Niclou, Simone P.; Pasero, Philippe; Calsou, Patrick; Masson, Jean‐Yves; Britton, Sébastien; Dyck, Eric Van

doi:10.1093/nar/gkab785

Cited by 11 publications

(10 citation statements)

References 105 publications

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“…Not surprisingly, the pro-oncogenic role of RAD52 is especially pronounced in cancer cells that are deficient in DDR pathways, like ATM-deficient cancers ( Treuner et al, 2004 ). But the most remarkable pro-cancer RAD52 phenotype is seen in cancer cells deficient in any of the following DNA repair proteins: BRCA1, BRCA2, PALB2, XAB2 or RAD51 paralogs: RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3 ( Feng et al, 2011 ; Chun et al, 2013 ; Lok et al, 2013 ; Sharma et al, 2021 ). Powell’s group showed that cells in which one of these proteins were mutated or depleted became dependent on RAD52 for viability; thus, mutations in RAD52 are synthetically lethal with mutations/depletion in these proteins.…”

Section: Introductionmentioning

confidence: 99%

RAD52: Paradigm of Synthetic Lethality and New Developments

et al. 2021

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DNA double-strand breaks and inter-strand cross-links are the most harmful types of DNA damage that cause genomic instability that lead to cancer development. The highest fidelity pathway for repairing damaged double-stranded DNA is termed Homologous recombination (HR). Rad52 is one of the key HR proteins in eukaryotes. Although it is critical for most DNA repair and recombination events in yeast, knockouts of mammalian RAD52 lack any discernable phenotypes. As a consequence, mammalian RAD52 has been long overlooked. That is changing now, as recent work has shown RAD52 to be critical for backup DNA repair pathways in HR-deficient cancer cells. Novel findings have shed light on RAD52’s biochemical activities. RAD52 promotes DNA pairing (D-loop formation), single-strand DNA and DNA:RNA annealing, and inverse strand exchange. These activities contribute to its multiple roles in DNA damage repair including HR, single-strand annealing, break-induced replication, and RNA-mediated repair of DNA. The contributions of RAD52 that are essential to the viability of HR-deficient cancer cells are currently under investigation. These new findings make RAD52 an attractive target for the development of anti-cancer therapies against BRCA-deficient cancers.

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Section: Introductionmentioning

confidence: 99%

RAD52: Paradigm of Synthetic Lethality and New Developments

et al. 2021

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“…Combined depletion experiments did not lead to enhanced defects in HR or SSA suggesting that XAB2, ISY1 and PRP19 could function together to promote DSB repair. More recently, XAB2 was also identified in an shRNA-targeted screen for genes involved in temozolomide (TMZ) resistance [ 122 ]. XAB2 depletion impaired DSB repair and fork progression in the presence of CPT suggesting a role in single-ended DSB repair.…”

Section: Regulation Of Dsb Resection By Ntc Complex Membersmentioning

confidence: 99%

The PRP19 Ubiquitin Ligase, Standing at the Cross-Roads of mRNA Processing and Genome Stability

Idrissou

Maréchal

2022

Cancers

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mRNA processing factors are increasingly being recognized as important regulators of genome stability. By preventing and resolving RNA:DNA hybrids that form co-transcriptionally, these proteins help avoid replication–transcription conflicts and thus contribute to genome stability through their normal function in RNA maturation. Some of these factors also have direct roles in the activation of the DNA damage response and in DNA repair. One of the most intriguing cases is that of PRP19, an evolutionarily conserved essential E3 ubiquitin ligase that promotes mRNA splicing, but also participates directly in ATR activation, double-strand break resection and mitosis. Here, we review historical and recent work on PRP19 and its associated proteins, highlighting their multifarious cellular functions as central regulators of spliceosome activity, R-loop homeostasis, DNA damage signaling and repair and cell division. Finally, we discuss open questions that are bound to shed further light on the functions of PRP19-containing complexes in both normal and cancer cells.

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“…However, fully active HR outcompetes NHEJ for the repair of seDSBs in S/G2 [ 61 ]. Several studies have underlined the involvement of HR in the repair of lesions resulting from O 6 -meG adducts [ 62 , 63 , 64 ].…”

Section: Dna Repair Mechanisms Promoting Resistance To Ir and Alkylating Agent Therapymentioning

confidence: 99%

“…At the same time, our catalogue of small molecule inhibitors targeting DNA repair is expanding rapidly [ 225 , 226 , 227 , 228 ] while novel targets are being discovered for the sensitization of glioma cells to radio- and chemotherapy [ 21 , 22 ]. These include RAD52 whose depletion led to TMZ hypersensitivity in GBM cells [ 64 ]. Carruthers et al found that adult GBM stem-like cells display high levels of DNA replication stress driving constitutive DDR activation and radiation resistance [ 229 ].…”

Section: Strategies Targeting Chromatin Dynamics and Dna Repair In Phggsmentioning

confidence: 99%

Impact of Chromatin Dynamics and DNA Repair on Genomic Stability and Treatment Resistance in Pediatric High-Grade Gliomas

Pinto

Baidarjad

Entz‐Werlé³

et al. 2021

Cancers

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Despite their low incidence, pediatric high-grade gliomas (pHGGs), including diffuse intrinsic pontine gliomas (DIPGs), are the leading cause of mortality in pediatric neuro-oncology. Recurrent, mutually exclusive mutations affecting K27 (K27M) and G34 (G34R/V) in the N-terminal tail of histones H3.3 and H3.1 act as key biological drivers of pHGGs. Notably, mutations in H3.3 are frequently associated with mutations affecting ATRX and DAXX, which encode a chaperone complex that deposits H3.3 into heterochromatic regions, including telomeres. The K27M and G34R/V mutations lead to distinct epigenetic reprogramming, telomere maintenance mechanisms, and oncogenesis scenarios, resulting in distinct subgroups of patients characterized by differences in tumor localization, clinical outcome, as well as concurrent epigenetic and genetic alterations. Contrasting with our understanding of the molecular biology of pHGGs, there has been little improvement in the treatment of pHGGs, with the current mainstays of therapy—genotoxic chemotherapy and ionizing radiation (IR)—facing the development of tumor resistance driven by complex DNA repair pathways. Chromatin and nucleosome dynamics constitute important modulators of the DNA damage response (DDR). Here, we summarize the major DNA repair pathways that contribute to resistance to current DNA damaging agent-based therapeutic strategies and describe the telomere maintenance mechanisms encountered in pHGGs. We then review the functions of H3.3 and its chaperones in chromatin dynamics and DNA repair, as well as examining the impact of their mutation/alteration on these processes. Finally, we discuss potential strategies targeting DNA repair and epigenetic mechanisms as well as telomere maintenance mechanisms, to improve the treatment of pHGGs.

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XAB2 promotes Ku eviction from single-ended DNA double-strand breaks independently of the ATM kinase

Cited by 11 publications

References 105 publications

RAD52: Paradigm of Synthetic Lethality and New Developments

RAD52: Paradigm of Synthetic Lethality and New Developments

The PRP19 Ubiquitin Ligase, Standing at the Cross-Roads of mRNA Processing and Genome Stability

Impact of Chromatin Dynamics and DNA Repair on Genomic Stability and Treatment Resistance in Pediatric High-Grade Gliomas

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