Break-Induced Replication Repair of Damaged Forks Induces Genomic Duplications in Human Cells

Costantino, Lorenzo; Sotiriou, Sotirios K.; Rantala, Juha; Magin, Simon; Mladenov, Emil; Helleday, Thomas; Haber, James E.; Iliakis, George; Kallioniemi, Olli; Halazonetis, Thanos D.

doi:10.1126/science.1243211

Cited by 413 publications

(417 citation statements)

References 41 publications

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“…One-ended breaks are recognized triggers of LTGC/BIR in yeast and in mammalian cells. 20,28,30,31,38 In response to an I-SceI-induced DSB, arrays containing 9 or more Ter sites resulted in progressive reductions in both STGC and LTGC,. With a larger Ter array, the distance between the I-SceI site and GFP sequences to the left of the Ter array increases (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…17,19,20 LTGC shares several properties with break-induced replication (BIR), a known mediator of genomic instability in yeast. [27][28][29][30][31] Indeed in BRCA1 mutant cells, LTGC is the most abundant HR product observed at Tus/Ter-stalled forks. Thus, determining the mechanisms underlying Tus/Ter-induced LTGC is crucial to understanding how the BRCA genes, and the HR machinery in general, suppress genomic instability at stalled replication forks.…”

Section: Introductionmentioning

confidence: 99%

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Spatial separation of replisome arrest sites influences homologous recombination quality at a Tus/Ter-mediated replication fork barrier

Willis

Scully

2016

Cell Cycle

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The Escherichia coli replication fork arrest complex Tus/Ter mediates site-specific replication fork arrest and homologous recombination (HR) on a mammalian chromosome, inducing both conservative "short tract" gene conversion (STGC) and error-prone "long tract" gene conversion (LTGC) products. We showed previously that bidirectional fork arrest is required for the generation of STGC products at Tus/Ter-stalled replication forks and that the HR mediators BRCA1, BRCA2 and Rad51 mediate STGC but suppress LTGC at Tus/Ter-arrested forks. Here, we report the impact of Ter array length on Tus/Ter-induced HR, comparing HR reporters containing arrays of 6, 9, 15 or 21 Ter sites-each targeted to the ROSA26 locus of mouse embryonic stem (ES) cells. Increasing Ter copy number within the array beyond 6 did not affect the magnitude of Tus/Ter-induced HR but biased HR in favor of LTGC. A "lock"-defective Tus mutant, F140A, known to exhibit higher affinity than wild type (wt)Tus for duplex Ter, reproduced these effects. In contrast, increasing Ter copy number within the array reduced HR induced by the I-SceI homing endonuclease, but produced no consistent bias toward LTGC. Thus, the mechanisms governing HR at Tus/Ter-arrested replication forks are distinct from those governing HR at an enzyme-induced chromosomal double strand break (DSB). We propose that increased spatial separation of the 2 arrested forks encountering an extended Tus/Ter barrier impairs the coordination of DNA ends generated by the processing of the stalled forks, thereby favoring aberrant LTGC over conservative STGC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Spatial separation of replisome arrest sites influences homologous recombination quality at a Tus/Ter-mediated replication fork barrier

Willis

Scully

2016

Cell Cycle

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“…Last, another mechanism by which RS could be involved on the generation of copy number alterations has also been recently described. This work revealed that break induced replication (BIR) is essential for cells to cope with RS induced by the overexpression of Cyclin E [39]. BIR is a specialized system of homologous recombination that can be used when the homology is limited to one side of the break, which is the case at a collapsed replication fork [40].…”

Section: Chromosomal Instability As a Results Of Replication Stressmentioning

confidence: 99%

“…For DNA synthesis, BIR employs the basic DNA replication machinery, but in addition it specifically depends on the DNA Polymerase accessory subunits POLD3 and POLD4. The reduction in the levels of either of these proteins in cells overexpressing Cyclin E reduces fork speed, increases fork collapse, blocks the generation of small amplifications and ultimately limits the proliferation of these cells [39]. To what extent POLD3 or POLD4 are non-essential in the context of primary cells demands further study.…”

Section: Chromosomal Instability As a Results Of Replication Stressmentioning

confidence: 99%

Replication stress and cancer: It takes two to tango

Lecona

Fernández-Capetillo

2014

Experimental Cell Research

119

107

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Problems arising during DNA replication require the activation of the ATR-CHK1 pathway to ensure the stabilization and repair of the forks, and to prevent the entry into mitosis with unreplicated genomes. Whereas the pathway is essential at the cellular level, limiting its activity is particularly detrimental for some cancer cells. Here we review the links between replication stress (RS) and cancer, which provide a rationale for the use of ATR and Chk1 inhibitors in chemotherapy. First, we describe how the activation of oncogene-induced RS promotes genome rearrangements and chromosome instability, both of which could potentially fuel carcinogenesis. Next, we review the various pathways that contribute to the suppression of RS, and how mutations in these components lead to increased cancer incidence and/or accelerated ageing. Finally, we summarize the evidence showing that tumours with high levels of RS are dependent on a proficient RS-response, and therefore vulnerable to ATR or Chk1 inhibitors.

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“…The POLD3 subunit interacts with the DNA polymerase clamp ring, called proliferating cell nuclear antigen (PCNA), which may also influence the processivity and fidelity of the four-subunit form. POLD3 was recently identified as a gene product that helps ameliorate the consequences of DNA breaks formed under replication stress conditions (16). This might be related to POLD3's role as a subunit of Pol δ, but now the potential role of Pol ζ in preventing break formation under stress conditions should be considered.…”

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confidence: 99%