Abstract
The caps on the ends of chromosomes, called telomeres, keep the ends of chromosomes from appearing as DNA double-strand breaks (DSBs) and prevent chromosome fusion. However, subtelomeric regions are sensitive to DSBs, which in normal cells is responsible for ionizing radiation-induced cell senescence and protection against oncogene-induced replication stress, but promotes chromosome instability in cancer cells that lack cell cycle checkpoints. We have previously reported that I-SceI endonuclease-induced DSBs near telomeres in a human cancer cell line are much more likely to generate large deletions and gross chromosome rearrangements (GCRs) than interstitial DSBs, but found no difference in the frequency of I-SceI-induced small deletions at interstitial and subtelomeric DSBs. We now show that inhibition of MRE11 3′–5′ exonuclease activity with Mirin reduces the frequency of large deletions and GCRs at both interstitial and subtelomeric DSBs, but has little effect on the frequency of small deletions. We conclude that large deletions and GCRs are due to excessive processing of DSBs, while most small deletions occur during classical nonhomologous end joining (C-NHEJ). The sensitivity of subtelomeric regions to DSBs is therefore because they are prone to undergo excessive processing, and not because of a deficiency in C-NHEJ in subtelomeric regions.
Highlights
DNA double-strand breaks (DSBs) from extracellular origins, such as ionizing radiation (IR) or chemotherapeutic drugs, or from intracellular origins, such as replication fork collapse or reactive oxygen species, are very hazardous to cells (1)
To address our hypothesis that excessive processing is the reason that subtelomeric DSBs are highly prone to large deletions and gross chromosome rearrangements (GCRs), we investigated the role of Meiotic Recombination 11 Homolog (MRE11) in the formation of mutations at interstitial and subtelomeric DSBs
We propose that large deletions and GCRs at both interstitial and subtelomeric DSBs are a result of excessive processing (Figure 6)
Summary
DNA double-strand breaks (DSBs) from extracellular origins, such as ionizing radiation (IR) or chemotherapeutic drugs, or from intracellular origins, such as replication fork collapse or reactive oxygen species, are very hazardous to cells (1). DSBs can be repaired through pathways that involve the binding of the MRE11-RAD50-NBS1 (MRN) complex. The MRN/ATM pathway is involved in the processing of DSBs, which is required for homologous recombination repair (HRR) and alternative NHEJ (A-NHEJ). The processing of DSBs results in the formation of a 3 single-stranded overhang, which involves the nuclease activity of the Meiotic Recombination 11 Homolog (MRE11) and CtBP-Interacting Protein (CtIP) (8,9). During late S and early G2 phase, ATM and Cyclin Dependent Kinase (CDK) function together in the activation of CtIP (13,14), which, like MRE11, contains nuclease activity used in processing DSBs (15). The processing of DSBs by MRE11 and CtIP is followed by extensive resection of the 5 ends of the DSB by the nuclease activity of Exonuclease 1 (EXOI) or the BLM-DNA2 complex (16–18). A-NHEJ involves joining at sites with or without micro-
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