p21<sup>WAF1/Cip1</sup> - PCNA: Fatal attraction

Galanos, Panagiotis; Pappas, George D.; Gorgoulis, Vassilis G.

doi:10.1080/15384101.2016.1216930

Cited by 2 publications

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“…Given the low levels of pivotal components (Rad51, BRCA1, and BRCA2) of the SDSA repair machinery (Fig. 4c, d ; Additional file 1 : Figure S6a), the p21 WAF1/Cip1 expressing cells resort to transcriptional upregulation of Rad52, a fact that reflects the increased repair needs required to cope with the p21 WAF1/Cip1 -driven replication stress [ 61 ] . On the other hand, post-translational modifications of the chromatin bound fraction of Rad52 cannot be excluded, as recently reported [ 49 ], and could further contribute to increased abundance of Rad52.…”

Section: Discussionmentioning

confidence: 99%

Mutational signatures reveal the role of RAD52 in p53-independent p21-driven genomic instability

et al. 2018

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BackgroundGenomic instability promotes evolution and heterogeneity of tumors. Unraveling its mechanistic basis is essential for the design of appropriate therapeutic strategies. In a previous study, we reported an unexpected oncogenic property of p21WAF1/Cip1, showing that its chronic expression in a p53-deficient environment causes genomic instability by deregulation of the replication licensing machinery.ResultsWe now demonstrate that p21WAF1/Cip1 can further fuel genomic instability by suppressing the repair capacity of low- and high-fidelity pathways that deal with nucleotide abnormalities. Consequently, fewer single nucleotide substitutions (SNSs) occur, while formation of highly deleterious DNA double-strand breaks (DSBs) is enhanced, crafting a characteristic mutational signature landscape. Guided by the mutational signatures formed, we find that the DSBs are repaired by Rad52-dependent break-induced replication (BIR) and single-strand annealing (SSA) repair pathways. Conversely, the error-free synthesis-dependent strand annealing (SDSA) repair route is deficient. Surprisingly, Rad52 is activated transcriptionally in an E2F1-dependent manner, rather than post-translationally as is common for DNA repair factor activation.ConclusionsOur results signify the importance of mutational signatures as guides to disclose the repair history leading to genomic instability. We unveil how chronic p21WAF1/Cip1 expression rewires the repair process and identifies Rad52 as a source of genomic instability and a candidate therapeutic target.Electronic supplementary materialThe online version of this article (10.1186/s13059-018-1401-9) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Mutational signatures reveal the role of RAD52 in p53-independent p21-driven genomic instability

et al. 2018

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Mutational signatures reveal the role of RAD52 in p53-independent p21 driven genomic instability

Galanos

Pappas

Polyzos

et al. 2017

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p21^WAF1/Cip1 - PCNA: Fatal attraction

Abstract: Feature to: Galanos P, et al. Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing. Nat Cell Biol 2016; 18(7):777-89; PMID: 27323328; http://dx

Cited by 2 publications

References 7 publications

Mutational signatures reveal the role of RAD52 in p53-independent p21-driven genomic instability

Mutational signatures reveal the role of RAD52 in p53-independent p21-driven genomic instability

Mutational signatures reveal the role of RAD52 in p53-independent p21 driven genomic instability

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p21WAF1/Cip1 - PCNA: Fatal attraction

Abstract: Feature to: Galanos P, et al. Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing. Nat Cell Biol 2016; 18(7):777-89; PMID: 27323328; http://dx

Cited by 2 publications

References 7 publications

Mutational signatures reveal the role of RAD52 in p53-independent p21-driven genomic instability

Mutational signatures reveal the role of RAD52 in p53-independent p21-driven genomic instability

Mutational signatures reveal the role of RAD52 in p53-independent p21 driven genomic instability

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p21^WAF1/Cip1 - PCNA: Fatal attraction