POLθ-mediated end joining is restricted by RAD52 and BRCA2 until the onset of mitosis

Llorens-Agost, Marta; Ensminger, Michael; Le, Hang Phuong; Gawai, Anugrah; Liu, Jie; Cruz-García, Andrés; Bhetawal, Sarita; Wood, Richard D.; Heyer, Wolf Dietrich; Löbrich, Markus

doi:10.1038/s41556-021-00764-0

Cited by 75 publications

(51 citation statements)

References 47 publications

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“…TMEJ, on the other hand, still uses microhomologies, but also relies on Pol θ in order to prime the synthesis of up to 25 nt of nascent DNA (Hanscom and McVey, 2020). More recently, TMEJ has been shown to be cell cycle regulated, repairing one-ended DSBs that arise in S-phase in early mitosis (Llorens-Agost et al, 2021). In this pathway, RAD52 and BRCA2 delay TMEJ until early mitosis, by which time one-ended DSBs have been converted to twoended DSBs.…”

Section: Downstream Double Strand Break Repair Pathwaysmentioning

confidence: 99%

Immediate-Early, Early, and Late Responses to DNA Double Stranded Breaks

Kieffer

Lowndes

2022

Front. Genet.

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Loss or rearrangement of genetic information can result from incorrect responses to DNA double strand breaks (DSBs). The cellular responses to DSBs encompass a range of highly coordinated events designed to detect and respond appropriately to the damage, thereby preserving genomic integrity. In analogy with events occurring during viral infection, we appropriate the terms Immediate-Early, Early, and Late to describe the pre-repair responses to DSBs. A distinguishing feature of the Immediate-Early response is that the large protein condensates that form during the Early and Late response and are resolved upon repair, termed foci, are not visible. The Immediate-Early response encompasses initial lesion sensing, involving poly (ADP-ribose) polymerases (PARPs), KU70/80, and MRN, as well as rapid repair by so-called ‘fast-kinetic’ canonical non-homologous end joining (cNHEJ). Initial binding of PARPs and the KU70/80 complex to breaks appears to be mutually exclusive at easily ligatable DSBs that are repaired efficiently by fast-kinetic cNHEJ; a process that is PARP-, ATM-, 53BP1-, Artemis-, and resection-independent. However, at more complex breaks requiring processing, the Immediate-Early response involving PARPs and the ensuing highly dynamic PARylation (polyADP ribosylation) of many substrates may aid recruitment of both KU70/80 and MRN to DSBs. Complex DSBs rely upon the Early response, largely defined by ATM-dependent focal recruitment of many signalling molecules into large condensates, and regulated by complex chromatin dynamics. Finally, the Late response integrates information from cell cycle phase, chromatin context, and type of DSB to determine appropriate pathway choice. Critical to pathway choice is the recruitment of p53 binding protein 1 (53BP1) and breast cancer associated 1 (BRCA1). However, additional factors recruited throughout the DSB response also impact upon pathway choice, although these remain to be fully characterised. The Late response somehow channels DSBs into the appropriate high-fidelity repair pathway, typically either ‘slow-kinetic’ cNHEJ or homologous recombination (HR). Loss of specific components of the DSB repair machinery results in cells utilising remaining factors to effect repair, but often at the cost of increased mutagenesis. Here we discuss the complex regulation of the Immediate-Early, Early, and Late responses to DSBs proceeding repair itself.

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Section: Downstream Double Strand Break Repair Pathwaysmentioning

confidence: 99%

Immediate-Early, Early, and Late Responses to DNA Double Stranded Breaks

Kieffer

Lowndes

2022

Front. Genet.

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“…Poly-ADP ribose polymerase-1 (PARP1) and DNA polymerase θ anneal microhomologies (∼10 bp) between DNA ends, followed by XRCC1- and DNA ligase III-mediated end processing ( Srinivasan et al, 2019 ) that generate an intact DNA molecule. a-EJ was reported to be partially dependent on RAD52, likely through RAD52’s annealing activity ( Kan et al, 2017 ; Hendrickson 2020 ), which prevents premature usage of a-EJ until the cell enters mitosis ( Llorens-Agost et al, 2021 ). RAD52 also inhibits PARP-mediated single-strand break repair by interfering with colocalization of XRCC1 and DNA ligase III ( Wang et al, 2021 ).…”

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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“…Such regions contain ultra-fine DNA bridges [ 119 ], which may link chromosome fragments created by DSBs. Further, our identified role for PolQ in mitosis is relevant to human cancer, as cancer cells lacking the BRCA2 or RAD52 repair proteins rely heavily on PolQ-mediated alt-EJ repair in mitosis ( Figure 2 C) [ 120 ]. Taken together, it is clear that mitotic cell cycle stage, developmental stage, cell type, and organism type all influence DDR responses.…”

Section: Ddr Responses During the Mitotic Cell Cycle Across Model Systemsmentioning

confidence: 99%

DNA Damage Responses during the Cell Cycle: Insights from Model Organisms and Beyond

Clay

Fox

2021

Genes

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Genome damage is a threat to all organisms. To respond to such damage, DNA damage responses (DDRs) lead to cell cycle arrest, DNA repair, and cell death. Many DDR components are highly conserved, whereas others have adapted to specific organismal needs. Immense progress in this field has been driven by model genetic organism research. This review has two main purposes. First, we provide a survey of model organism-based efforts to study DDRs. Second, we highlight how model organism study has contributed to understanding how specific DDRs are influenced by cell cycle stage. We also look forward, with a discussion of how future study can be expanded beyond typical model genetic organisms to further illuminate how the genome is protected.

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POLθ-mediated end joining is restricted by RAD52 and BRCA2 until the onset of mitosis

Cited by 75 publications

References 47 publications

Immediate-Early, Early, and Late Responses to DNA Double Stranded Breaks

Immediate-Early, Early, and Late Responses to DNA Double Stranded Breaks

RAD52: Paradigm of Synthetic Lethality and New Developments

DNA Damage Responses during the Cell Cycle: Insights from Model Organisms and Beyond

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