p53: traffic cop at the crossroads of DNA repair and recombination

Abstract

p53 mutants that lack DNA-binding activities, and therefore, transcriptional activities, are among the most common mutations in human cancer. Recently, a new role for p53 has come to light, as the tumour suppressor also functions in DNA repair and recombination. In cooperation with its function in transcription, the transcription-independent roles of p53 contribute to the control and efficiency of DNA repair and recombination.

Crosstalk between site-specific modifications on p53 and histone H3

“…This data suggests that acetylation at histone H3, K9 is associated with de-phosphorylation at S37. Our overall findings are consistent with and confirm the hypothesis that stress-induced changes in p53 phosphorylation may alter patterns of histone post-translational modification (Allison and Milner, 2003;Sengupta and Harris, 2005). Use of site-specific p53 phosphorylation mutants has allowed us to pinpoint p53 phosphorylation sites, such as S37, that appear crucial for histone H3 modification.…”

“…p53 is thought to function as the 'molecular node' connecting upstream signaling cascades and downstream DNA-repair-recombination pathways. The role of p53 in genomic global repair is now well established (see Sengupta and Harris, 2005, for review). DNA repair and gene transactivation also require histone acetylation (Zhang and Dent, 2005).…”

TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer

“…TP53 mutations and HCC SP Hussain et al in the formation of DNA repair protein complexes and transcriptional transactivation of DNA repair genes (Sengupta and Harris, 2005), and to extensive DNA damage by mediating cell death, p53 also contributes to these processes by switching from increased expression of anti-to pro-oxidant genes. p53 can both transcriptionally transrepress pro-oxidant/nitrosative genes, for example, nitric oxide synthases (NOS)2, and transactivate antioxidant genes expressing glutathione peroxidase, aldehyde dehydrogenase, and Mn-superoxide dismutase, sestrins, and TIGAR (TP53-induced glycolysis and apoptosis regulator) (Table 4).…”

p53 suppression overwhelms DNA polymerase η deficiency in determining the cellular UV DNA damage response

“…These arrested replication forks contain long (several kB) regions of single-stranded DNA, which are covered by RPA which in turn binds p53, ATRIP/ATR and other proteins [42,[47][48][49]. Competition between p53 and these other factors at the ssDNA regions plays a complex role the intra-S-phase checkpoint [18], producing varied results depending on the cell types and transformed status.…”

“…These alternative mechanisms involve the use of alternative polymerases such as Pol ι [16] or recombination between sister chomatids [17]. Several lines of evidence suggest that p53 plays a major role in mediating downstream events associated with S phase arrest from UV damage [18], especially in XP-V cells with protracted S phase arrest due to Pol η deficiency [19]. XP-V cells, in which p53 function was abrogated due to viral transformation by HPV16 (E6) [20,21] or SV40 [22], demonstrated a dramatic increase in sensitivity to the lethal and cytogenetic effects of UV light [23].…”