DNA repair and chromosomal alterations

Adayapalam T Natarajan, Fabrizio Palitti
Mutation Research 2008 November 17, 657 (1): 3-7
All mutagenic agents induce lesions in the cellular DNA and they are repaired efficiently by different repair mechanisms. Un-repaired and mis-repaired lesions lead to chromosomal aberrations (CAs). Depending upon the mutagenic agents involved, different DNA repair pathways, such as nucleotide excision repair (NER), base excision repair (BER), non-homologous end joining (NHEJ), homologous recombination repair (HRR), cross-link repair (FANC), single strand annealing (SSA) etc., are operative. Following ionising radiation, DNA double strand breaks (DSBs, which are considered to be the most important leasion leading to observed biological effects) are repaired either by NHEJ and/or HRR. We have investigated the relative role of these two repair pathways leading to chromosomal aberrations using Chinese hamster ovary (CHO) mutant cells deficient in one of these two repair pathwatys. NHEJ operates both in G1 and G2 phases of the cell cycle, wheras HHR operates mainly in S and G2 phases of the cell cycle. In NHEJ-deficient mutant cells irradiated in G1, un-repaired double strand breaks reaching S phase are repaired (unexpectedly with a large mis-repair component) by HRR. In HRR-deficient mutant cells, un-repaired DSBs reaching S phase are repaired by NHEJ (unexpectedly with a low mis-repair component) as evidenced by the frequencies of chromatid type aberrations. Employing a similar approach, following treatment with benzo(alpha)pyrene-7,8diol-9,10epoxide (BPDE), the active metabolite of benzo(alpha)pyrene, NER and HRR seem to be the most important repair pathways protecting against chromosomal damage induced by this agent. In the case of acetaldehyde, (primary metabolite of alcohol in vivo) a DNA cross-linking agent, HRR and FANC pathways are important for protection against damage induced by this agent. Irrespective of the type of DNA lesions induced, ultimately they have to be converted to DSBs in order to give rise to CA. Therefore, both NHEJ and HRR are also involved to some extent in the origin of CA following treatment with S-dependent agents.The relative importance of different repair pathways in bestowing protection against DNA damage leading to chromosomal alterations is discussed.

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