p53's double life: transactivation-independent repression of homologous recombination

Abstract

The tumor suppressor protein p53 controls cell cycle checkpoints and apoptosis via the transactivation of several genes. However, data from various laboratories suggest an additional role for p53: transcription-independent suppression of homologous recombination (HR). Genetic and physical interactions among p53, HR proteins (e.g. RAD51 and RAD54) and HR-DNA intermediates show that p53 acts directly on HR during the early and late steps of recombination. Complementary to the MSH2 mismatch-repair system, p53 appears to impair excess HR by controlling the minimal efficiency processing segment and by reversing recombination intermediates. By controlling the balance between the BLM and the RAD51 pathways, this direct role of p53 could maintain genome stability when replication forks are stalled at regions of DNA damage. In this article, we discuss the direct role of p53 on HR and the consequences for genome stability, tumor protection and speciation.

HIV-1 Vpr induces ATM-dependent cellular signal with enhanced homologous recombination

“…It has been proposed that during the DSB repair process, Rad51 is released from a complex of p53 and becomes competent for HR Bertrand et al, 2004). To address this possibility, we compared the physical association of Rad51 and p53 in the insoluble chromatin fraction before and after the induction of Vpr expression.…”

XRCC4 in G1 suppresses homologous recombination in S/G2, in G1 checkpoint-defective cells

“…The latter hypothesis is supported by the observation that the frequency of Rad51 focipositive cells was higher with XRCC4 À cells irradiated in G1 compared to G2, whereas this was not the case with complemented cells (see Figure 2b). Finally, p53 protein controls the G1 checkpoint but also directly prevents excess of GC, thus protecting against genome rearrangements, in two complementary ways (for review, Bertrand et al, 2004). Consequently, in double NHEJ-and p53-defective cells, HR might participate in the generation of complicons.…”

“…Defects in HR or in NHEJ can lead to genome instability and tumorigenesis (Liu et al, 1998;Sonoda et al, 1998;Difilippantonio et al, 2000;Ferguson et al, 2000a;Bertrand et al, 2003). However, both functional HR and NHEJ can be responsible for genome rearrangements: (i) functional HR between repeated sequences dispersed through the genome can also lead to genome rearrangements (Purandare and Patel, 1997;Richardson and Jasin, 2000b;Bertrand et al, 2004), and (ii) functional Ku autoantigen protein (KU)-dependent as well as KU-independent NHEJ can generate genetic rearrangements (Guirouilh-Barbat et al, 2004). This shows the importance of a precise DSB repair regulation in mammalian cells for the equilibrium between genetic stability and diversity.…”

JAK2V617F negatively regulates p53 stabilization by enhancing MDM2 via La expression in myeloproliferative neoplasms

“…Inactivation of the p53 tumor suppressor protein, which has demonstrated pleiotropic functions in cell cycle, apoptosis and DNA repair (Smith and Seo, 2002;Bertrand et al, 2004), could also favor homologous recombination (Akyuz et al, 2002;Bertrand et al, 2004). p53-inactivating mutations were identified in o15% of chronic phase hematological malignancies, including chronic myelogenous leukemia (Kantarjian et al, 1987;Feinstein et al, 1991;Hernandez-Boussard et al, 1999), PV (Gaidano et al, 1997) and PMF (Tsurumi et al, 2002;Reilly, 2005) and more than half of MPN in blast crisis (Gaidano et al, 1997;Tsurumi et al, 2002).…”