High-resolution genomic assays provide insight into the division of labor between TLS and HDR in mammalian replication of damaged DNA.
The multitude of DNA lesions that continuously form in DNA cannot all be detected and removed prior to replication. Thus, encounters of the replication fork with DNA damage become inevitable. Such encounters inhibit fork progression, leading to replication fork arrest or to replication re-priming downstream of the damage site. Either of these events will result in the formation of gap-lesion structures, in which a damaged base is located in a single stranded stretch of DNA, that is vulnerable to subsequent nicking. The double strand break that would ensue if ssDNA becomes nicked constitutes escalation of the damage from nucleotide(s)-specific to chromosomal scale. Cells employ two universal DNA damage tolerance (DDT) strategies to resolve these situations, by converting the gap-lesion structures into dsDNA without repairing the damage. The first is translesion DNA synthesis (TLS), in which a specialized low-fidelity DNA polymerase inserts a nucleotide opposite the damaged one. TLS is inherently mutagenic, due to the miscoding nature of most damaged nucleotides. The second strategy is homology-dependent repair (HDR), which relies on the presence of an identical intact sister chromatid. The molecular mechanisms that regulate the division of labor between these pathways are poorly understood. This review focuses on the balance between TLS and HDR in mammalian cells, discussing recent findings that were made possible thanks to newly developed high resolution genomic assays, and highlighting the role of the DNA lesion's properties in DDT pathway choice.
Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel. Electronic address: zvi.livneh@weizmann.ac.il.
Zvi
Z
Livneh
Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel.
Isadora S
IS
Cohen
Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel.
Tamar
T
Paz-Elizur
Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel.
Dana
D
Davidovsky
Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel.
Dalit
D
Carmi
Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel.
Umakanta
U
Swain
Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel.
Nataly
N
Mirlas-Neisberg
D000818:Animals; D020137:Base Pair Mismatch; D001681:Biological Assay; D020134:Catalytic Domain; D004247:DNA / Q000235:genetics* / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D059766:DNA End-Joining Repair; D053843:DNA Mismatch Repair; D004261:DNA Replication; D004277:DNA, Single-Stranded / Q000235:genetics* / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008957:Models, Genetic; D059767:Recombinational DNA Repair; D014466:Ultraviolet Rays
D004277:DNA, Single-Stranded; D004247:DNA; D004259:DNA-Directed DNA Polymerase
CPD; DNA damage; Postreplication repair; Recombination; TLS; Template switch; UV lesions