Essential Roles for Polymerase θ-Mediated End Joining in the Repair of Chromosome Breaks

Wyatt, David W.; Feng, Wei; Conlin, Michael P.; Yousefzadeh, Matthew J.; Roberts, Steven A.; Mieczkowski, Piotr A.; Wood, Richard D.; Gupta, Gaorav P.; Ramsden, Dale A.

doi:10.1016/j.molcel.2016.06.020

Cited by 257 publications

(387 citation statements)

References 31 publications

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“…Its polymerase activity can preserve 3´ overhangs on DSBs and use minimal base pairs to bridge broken DNA ends for 3´ extension (17, 18, 121) (Fig. 3c).…”

Section: The A-family Pol ν and θ In Dna End-joiningmentioning

confidence: 99%

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Translesion and Repair DNA Polymerases: Diverse Structure and Mechanism

Yang

Gao

2018

Annu. Rev. Biochem.

183

206

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The number of DNA polymerases identified in each organism has mushroomed in last two decades. Most newly found DNA polymerases specialize in translesion synthesis and DNA repair instead of replication. Although intrinsic error rates are higher for translesion and repair polymerases than for replicative polymerases, the specialized polymerases increase genome stability and reduce tumorigenesis. Reflecting the numerous types of DNA lesions and variations of broken DNA ends, translesion and repair polymerases differ in structure, mechanism and function. Here we review the unique and general features of polymerases specialized in lesion-bypass, gap-filling and end-joining synthesis.

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“…Its polymerase activity can preserve 3´ overhangs on DSBs and use minimal base pairs to bridge broken DNA ends for 3´ extension (17, 18, 121) (Fig. 3c).…”

Section: The A-family Pol ν and θ In Dna End-joiningmentioning

confidence: 99%

“…DSBs are repaired by homologous recombination, non-homologous end joining (NHEJ), or Pol θ-mediated end joining (TMEJ) (15–18). Both NHEJ and TMEJ depend on specialized polymerases to bridge DNA ends and fill small gaps before ligation.…”

Section: Introductionmentioning

confidence: 99%

Translesion and Repair DNA Polymerases: Diverse Structure and Mechanism

Yang

Gao

2018

Annu. Rev. Biochem.

183

206

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“…While it is not possible to determine which repair strategy is initially favored at the break, the efficiency of I-SceI cutting may ultimately select for HDR, since direct ligation would often restore the cut site, perhaps to be cut again. Once resected, annealing becomes the strongly favored strategy since long ssDNA tails are not ideal substrates for TMEJ or cNHEJ (Waters et al 2014;Wyatt et al 2016) and strand invasion is not possible. SSA represents .93% of all repair products in wild type and Marcal1 K275M heterozygotes, supporting this interpretation.…”

Section: Atp Binding Is Required For Marcal1 Activity During Sdsamentioning

confidence: 99%

“…EJ can also be used as an exit strategy after resection via microhomology-mediated EJ (MMEJ). In metazoans, this process requires DNA polymerase u, and has recently been called u-mediated EJ (TMEJ) (Figure 1, H and I) (Chan et al 2010;Yu and McVey 2010;Garcia et al 2011;Yousefzadeh et al 2014;Rodgers and McVey 2016;van Schendel et al 2016;Wyatt et al 2016).…”

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confidence: 99%

Annealing of Complementary DNA Sequences During Double-Strand Break Repair inDrosophilaIs Mediated by the Ortholog of SMARCAL1

Holsclaw

Sekelsky

2017

Genetics

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DNA double-strand breaks (DSBs) pose a serious threat to genomic integrity. If unrepaired, they can lead to chromosome fragmentation and cell death. If repaired incorrectly, they can cause mutations and chromosome rearrangements. DSBs are repaired using end-joining or homology-directed repair strategies, with the predominant form of homology-directed repair being synthesisdependent strand annealing (SDSA). SDSA is the first defense against genomic rearrangements and information loss during DSB repair, making it a vital component of cell health and an attractive target for chemotherapeutic development. SDSA has also been proposed to be the primary mechanism for integration of large insertions during genome editing with CRISPR/Cas9. Despite the central role for SDSA in genome stability, little is known about the defining step: annealing. We hypothesized that annealing during SDSA is performed by the annealing helicase SMARCAL1, which can anneal RPA-coated single DNA strands during replication-associated DNA damage repair. We used unique genetic tools in Drosophila melanogaster to test whether the fly ortholog of SMARCAL1, Marcal1, mediates annealing during SDSA. Repair that requires annealing is significantly reduced in Marcal1 null mutants in both synthesisdependent and synthesis-independent (single-strand annealing) assays. Elimination of the ATP-binding activity of Marcal1 also reduced annealing-dependent repair, suggesting that the annealing activity requires translocation along DNA. Unlike the null mutant, however, the ATP-binding defect mutant showed reduced end joining, shedding light on the interaction between SDSA and end-joining pathways.

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“…1a) (1)(2)(3). Understanding the biochemical activities and cellular functions of Polθ have become a priority because it has been found to be essential for the error-prone doublestrand break (DSB) repair pathway known as microhomology-mediated end-joining (MMEJ) or alternative end-joining (alt-EJ) (3)(4)(5)(6)(7)(8)(9). Remarkably, Polθ expression has also been shown to be important for the proliferation of cells deficient in the homologous recombination (HR) pathway, such as due to mutations in BRCA1 or BRCA2 (4,10).…”

mentioning

confidence: 99%