Mechanisms of direct replication restart at stressed replisomes

Conti, Brooke A.; Smogorzewska, Agata

doi:10.1016/j.dnarep.2020.102947

Cited by 24 publications

(28 citation statements)

References 194 publications

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“…As expected, replication of both pCtrl and pICL AP yielded only unmodified bottom strands (Fig. 1b and 1c, lanes [15][16][17][18][19][20][21][22][23][24]. In contrast, while pCtrl replication produced only an unmodified top strand, pICL AP replication produced an additional, slower-migrating top strand species, consistent with the presence of a peptide adduct (Fig.…”

Section: Hmces Forms a Dpc During Neil3-dependent Icl Repairsupporting

confidence: 75%

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The HMCES DNA-protein cross-link functions as a constitutive DNA repair intermediate

Semlow

MacKrell

Walter

2021

Preprint

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The HMCES protein forms a covalent DNA-protein cross-link (DPC) with abasic (AP) sites in ssDNA, and the resulting HMCES-DPC is thought to suppress double-strand break formation in S phase. However, the dynamics of HMCES cross-linking and whether any DNA repair pathways normally include an HMCES-DPC intermediate remain unknown. Here, we show that an HMCES-DPC forms efficiently on the AP site generated during replication-coupled DNA interstrand cross-link (ICL) repair. We use this system to show that HMCES cross-links form on DNA after the replicative CMG helicase has passed over the AP site, and that HMCES is subsequently removed by the SPRTN protease. The HMCES-DPC suppresses DSB formation, slows translesion synthesis (TLS) past the AP site, and introduces a bias for insertion of deoxyguanosine opposite the AP site. These data show that HMCES-DPCs can form as constitutive intermediates in replication-coupled repair, and they suggest a general model of how HMCES protects AP sites during DNA replication.

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Section: Hmces Forms a Dpc During Neil3-dependent Icl Repairsupporting

confidence: 75%

“…As expected, addition of rNEIL3, but not rNEIL3 K60A , resulted in rapid AP-ICL unhooking as indicated by conversion of cross-linked replication intermediates into open-circular and supercoiled products (Fig. 2c, lanes [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30].…”

Section: Hmces Suppresses Dsb Formation During Neil3-dependent Icl Repairmentioning

confidence: 57%

The HMCES DNA-protein cross-link functions as a constitutive DNA repair intermediate

Semlow

MacKrell

Walter

2021

Preprint

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“…Another possibility for the cell is to skip the block and resume DNA replication by synthesizing a new Okazaki fragment downstream of the RNAP complex ( Figure 4 A) [ 96 , 98 ]. This appears to be a simple and effective solution that takes advantage of the discontinuity of the lagging strand replication machinery to overcome obstacles on this DNA strand.…”

Section: Mechanisms To Resolve a Trcmentioning

confidence: 99%

“…This appears to be a simple and effective solution that takes advantage of the discontinuity of the lagging strand replication machinery to overcome obstacles on this DNA strand. However, for the leading strand, skipping and repriming imply the interruption and uncoupling of continuous DNA synthesis at the replication fork, thereby leaving stretches of ssDNA that will have to be filled by post-replicative repair pathways [ 96 , 98 ]. Repriming of the leading strand is executed by the intrinsic, although inefficient, ability of specialized DNA polymerases in both bacterial and eukaryotic cells [ 96 , 98 ].…”

Section: Mechanisms To Resolve a Trcmentioning

confidence: 99%

“…However, for the leading strand, skipping and repriming imply the interruption and uncoupling of continuous DNA synthesis at the replication fork, thereby leaving stretches of ssDNA that will have to be filled by post-replicative repair pathways [ 96 , 98 ]. Repriming of the leading strand is executed by the intrinsic, although inefficient, ability of specialized DNA polymerases in both bacterial and eukaryotic cells [ 96 , 98 ]. In human cells, this activity is achieved by the dual polymerase and primase activities of the PRIMPOL protein ( Figure 4 A) [ 99 , 100 ].…”

Section: Mechanisms To Resolve a Trcmentioning

confidence: 99%

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Consequences and Resolution of Transcription–Replication Conflicts

Lalonde

Trauner

Werner

et al. 2021

Life

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Transcription–replication conflicts occur when the two critical cellular machineries responsible for gene expression and genome duplication collide with each other on the same genomic location. Although both prokaryotic and eukaryotic cells have evolved multiple mechanisms to coordinate these processes on individual chromosomes, it is now clear that conflicts can arise due to aberrant transcription regulation and premature proliferation, leading to DNA replication stress and genomic instability. As both are considered hallmarks of aging and human diseases such as cancer, understanding the cellular consequences of conflicts is of paramount importance. In this article, we summarize our current knowledge on where and when collisions occur and how these encounters affect the genome and chromatin landscape of cells. Finally, we conclude with the different cellular pathways and multiple mechanisms that cells have put in place at conflict sites to ensure the resolution of conflicts and accurate genome duplication.

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