Mechanism, cellular functions and cancer roles of polymerase-theta-mediated DNA end joining

Ramsden, Dale A.; Carvajal-Garcia, Juan; Gupta, Gaorav P.

doi:10.1038/s41580-021-00405-2

Cited by 130 publications

(124 citation statements)

References 180 publications

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“…Alt-EJ encompasses vestigial NHEJ repair pathways that do not require KU70/80, XRCC4, or LIG4 (Figure 1F and Iliakis et al, 2015;Wyatt et al, 2016;Dutta et al, 2017;Hanscom and McVey, 2020;Ramsden et al, 2021). These repair subpathways occur after Artemis and CtIP-dependent slow-kinetic cNHEJ fails to repair the DSB, and when there is insufficient homology (less than 25 nt) for HR.…”

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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“…For instance, LIN37, a component of the DREAM transcriptional repressor, inhibits resection and HR in G0/G1-blocked pro-B cells by repressing the expression of HR proteins such as BRCA1, BRCA2, PALB2 and RAD51 ( Chen B. R. et al, 2021 ). Similarly, DNA polymerase theta (Pol θ, encoded by Polq in mice), implicated in alt-EJ ( Ramsden et al, 2021 ), is not expressed in G0/G1-arrested pro-B cells ( Figure 2Ci ) ( Yu et al, 2020 ).…”

Section: Blocking Dna End Resection and (Micro)homology-driven Double-strand Break Repairmentioning

confidence: 99%

The (Lack of) DNA Double-Strand Break Repair Pathway Choice During V(D)J Recombination

2022

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DNA double-strand breaks (DSBs) are highly toxic lesions that can be mended via several DNA repair pathways. Multiple factors can influence the choice and the restrictiveness of repair towards a given pathway in order to warrant the maintenance of genome integrity. During V(D)J recombination, RAG-induced DSBs are (almost) exclusively repaired by the non-homologous end-joining (NHEJ) pathway for the benefit of antigen receptor gene diversity. Here, we review the various parameters that constrain repair of RAG-generated DSBs to NHEJ, including the peculiarity of DNA DSB ends generated by the RAG nuclease, the establishment and maintenance of a post-cleavage synaptic complex, and the protection of DNA ends against resection and (micro)homology-directed repair. In this physiological context, we highlight that certain DSBs have limited DNA repair pathway choice options.

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“…The NHEJ process seems to be relatively simple and straightforward: it rejoins broken ends directly, without the requirement of long runs of end-resection and searching for a homologous repair template. NHEJ pathways are subdivided into the canonical NHEJ (c-NHEJ) and a group of less well elucidated alternative NHEJ (a-NHEJ) pathways, which are also called microhomology-mediated end-joining (MMEJ) or polymerase theta-mediated end-joining (TMEJ) [ 46 , 47 , 48 ]. Still, many factors are required for NHEJ pathways that demand precise cooperation and timely regulation ( Table 2 ).…”

Section: Dsb Repair Via Non-homologous End-joiningmentioning

confidence: 99%

DNA Double-Strand Break Repairs and Their Application in Plant DNA Integration

Shen

Zhao

2022

Genes

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Double-strand breaks (DSBs) are considered to be one of the most harmful and mutagenic forms of DNA damage. They are highly toxic if unrepaired, and can cause genome rearrangements and even cell death. Cells employ two major pathways to repair DSBs: homologous recombination (HR) and non-homologous end-joining (NHEJ). In plants, most applications of genome modification techniques depend on the development of DSB repair pathways, such as Agrobacterium-mediated transformation (AMT) and gene targeting (GT). In this paper, we review the achieved knowledge and recent advances on the DNA DSB response and its main repair pathways; discuss how these pathways affect Agrobacterium-mediated T-DNA integration and gene targeting in plants; and describe promising strategies for producing DSBs artificially, at definite sites in the genome.

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Mechanism, cellular functions and cancer roles of polymerase-theta-mediated DNA end joining

Cited by 130 publications

References 180 publications

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

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

The (Lack of) DNA Double-Strand Break Repair Pathway Choice During V(D)J Recombination

DNA Double-Strand Break Repairs and Their Application in Plant DNA Integration

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