NER and DDR: Classical music with new instruments

Abstract

Genomic insults by endogenous or exogenous sources activate the DNA damage response (DDR). After the recognition of damaged DNA by specific factors, repair mechanisms process the lesions, and a surveillance mechanism, known as DNA damage checkpoint, is triggered by single-stranded (ss) DNA covered by RPA. UV light induces DNA lesions, mainly 6,4 photoproducts (6-4PP) and cyclobutane pyrimidine dimers (CPD), which are removed by nucleotide excision repair (NER). Recent reports shed light onto the mechanism connecting NER and DDR after UV irradiation. How does UV-induced DNA damage activate checkpoint kinases? How is ssDNA generated at UV lesions? In yeast, UV lesions persisting during S phase represent a block for the advancing of replication forks, which temporarily stop and then reinitiate downstream of the damage, leaving a ssDNA region containing the lesion. Nonreplicating yeast and human cells with defects in NER are not able to properly activate the checkpoint cascade, indicating that processing of UV lesions is a prerequisite for checkpoint activation. This pathway also requires the function of exonuclease 1, which acts on NER intermediates generating long tracts of ssDNA. Here, we review the connections between NER processing of UV-induced lesions and checkpoint activation, discussing the role of recently identified players in this mechanism.

Genotoxic and mutagenic effects of lipid-coated CdSe/ZnS quantum dots

“…After induction of DNA damage by UV, DNA-repair mechanisms are induced in mammalian cells. They involve the induction of nucleotide-excision repair (NER), which removes photoproducts through a DNA-damage response (DDR) [60]. DDR is detected as DNA strand-breaks by the comet assay, and tends to increase the sensitivity of this test.…”

A UV-Induced Genetic Network Links the RSC Complex to Nucleotide Excision Repair and Shows Dose-Dependent Rewiring

“…The NER machinery, however, does not work in isolation. Increasing evidence points to the precise coordination of NER with several other biological processes such as the cell-cycle checkpoint (Sertic et al, 2012) and chromatin remodeling (Gong et al, 2006; Luijsterburg et al, 2012; Sarkar et al, 2010; Yu et al, 2005). Thus, a critical next step in defining the UV damage response will require an understanding of how distinct cellular processes cooperate with NER to promote the efficient repair of UV-induced lesions.…”

Homologous recombination rescues ssDNA gaps generated by nucleotide excision repair and reduced translesion DNA synthesis in yeast G2 cells

“…This coordination might prevent the conversion of ssDNA gaps into more deleterious DSBs, thereby preserving genome stability. In the event that long gaps are produced, surveillance mechanisms including checkpoint activation (13,14) may prevent cell-cycle progression until repair has been completed.…”