The switch from survival responses to apoptosis after chromosomal breaks.
Eukaryotic cells have evolved highly sophisticated cellular responses to DNA double strand breaks (DSBs) that increase the likelihood of survival. However, cells can also respond to DSBs by undergoing programmed cell death. The mechanisms underlying the cellular decision on whether to repair and survive or to die are not well understood but may be related to the efficiency of repair or the extent of the damage. Presumably, a few easily reparable DSBs will not result in cell death in most cell types. However, abundant complex DSBs will present a severe challenge to the repair machineries with repeated attempts at repair likely to result in genome instability. For multicellular eukaryotes at least, struggling to complete repair is folly, whereas removal of severely damaged cells is a more sensible strategy. Here we discuss recent evidence linking DSBs to a highly regulated form of cell death termed, apoptosis. In particular, we focus on the roles of the tumour suppressor, p53 and a recently discovered role for an isotype of the linker histone H1. We present a hypothesis that the elevated levels of ssDNA produced during ongoing attempts at DSB repair may be involved in the switch from repair to apoptosis.
Genome Stability Laboratory, Department of Biochemistry and National Centre for Biomedical Engineering Science, National University of Ireland Galway, University Road, Galway, Ireland.
Ronan T
RT
Bree
Catherine
C
Neary
Afshin
A
Samali
Noel F
NF
Lowndes
D000818:Animals; D017209:Apoptosis; D002467:Cell Nucleus / Q000378:metabolism; D002875:Chromosomes / Q000648:ultrastructure*; D004249:DNA Damage; D004260:DNA Repair; D004277:DNA, Single-Stranded; D016678:Genome; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000473:pathology; D008954:Models, Biological; D011499:Protein Processing, Post-Translational; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D015003:Yeasts / Q000378:metabolism
D004277:DNA, Single-Stranded; D006657:Histones; D016159:Tumor Suppressor Protein p53