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Genome Biol. 2018 Mar 16;19(1):37. doi: 10.1186/s13059-018-1401-9.

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

Author information

1
Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National Kapodistrian University of Athens, 75 Mikras Asias Str, GR-11527, Athens, Greece.
2
Danish Cancer Society Research Centre, Strandboulevarden 49, DK-2100, Copenhagen, Denmark.
3
Biomedical Research Foundation of the Academy of Athens, 4 Soranou Ephessiou Str, GR-11527, Athens, Greece.
4
Laboratory of Biology, School of Medicine, University of Patras, 26505, Patras, Rio, Greece.
5
Department of Biology, University of Padova, 35121, Padova, Italy.
6
Department of Biomolecular Sciences, Weizmann Institute of Science, 76100, Rehovot, Israel.
7
Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 48 Vassileos Constantinou Ave, GR-11635, Athens, Greece.
8
Physics Department, School of Applied Mathematical and Physical Sciences, National Technical University of Athens (NTUA), 15780, Zografou, Athens, Greece.
9
Department of Chemistry, New York University, New York, 10012, USA.
10
Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
11
Department of Radiation Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA.
12
Harvard Medical School, 25 Shattuck St, Boston, MA, 02115, USA.
13
Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaloes Vej 5, DK-2200, Copenhagen, Denmark.
14
Danish Cancer Society Research Centre, Strandboulevarden 49, DK-2100, Copenhagen, Denmark. jb@cancer.dk.
15
Science for Life Laboratory, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, SE-171 77, Stockholm, Sweden. jb@cancer.dk.
16
Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National Kapodistrian University of Athens, 75 Mikras Asias Str, GR-11527, Athens, Greece. vgorg@med.uoa.gr.
17
Biomedical Research Foundation of the Academy of Athens, 4 Soranou Ephessiou Str, GR-11527, Athens, Greece. vgorg@med.uoa.gr.
18
Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Wilmslow Road, Manchester, M20 4QL, UK. vgorg@med.uoa.gr.

Abstract

BACKGROUND:

Genomic 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.

RESULTS:

We 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.

CONCLUSIONS:

Our 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.

KEYWORDS:

Break-induced replication (BIR); Genomic instability; Rad52; Single nucleotide substitution (SNS); Single strand annealing (SSA); Translesion DNA synthesis (TLS); p21WAF1/Cip1

PMID:
29548335
PMCID:
PMC5857109
DOI:
10.1186/s13059-018-1401-9
[Indexed for MEDLINE]
Free PMC Article

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