Εξειδίκευση τύπου :	Άρθρο σε επιστημονικό περιοδικό
Τίτλος:	Mutational signatures reveal the role of RAD52 in p53-independent p21-driven genomic instability
Δημιουργός/Συγγραφέας:	Galanos P. Pappas G. Polyzos A. Kotsinas A. Svolaki I. Giakoumakis N.N. Glytsou C. Pateras I.S. Swain U. [EL] Σουλιώτης, Βασίλης Λ.[EN] Souliotis, Vassilis L. Georgakilas A.G. Geacintov N. Scorrano L. Lukas C. Lukas J. Livneh Z. Lygerou Z. Chowdhury D. Sørensen C.S. Bartek J. Gorgoulis V.G.
Εκδότης:	BioMed Central Ltd.
Ημερομηνία:	2018
Γλώσσα:	Αγγλικά
ISSN:	1474-7596
DOI:	10.1186/s13059-018-1401-9
Άλλο:	PubMed ID: 29548335
Περίληψη:	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.
Τίτλος πηγής δημοσίευσης:	Genome Biology
Τόμος/Κεφάλαιο:	19
Τεύχος:	1
Θεματική Κατηγορία:	[EL] Βιολογία (Γενικά)[EN] Biology (General) [EL] Βιοτεχνολογία[EN] Biotechnology
Λέξεις-Κλειδιά:	Break-induced replication (BIR) Genomic instability P21WAF1/Cip1 Rad52 Single nucleotide substitution (SNS) Single strand annealing (SSA) Translesion DNA synthesis (TLS)
Αξιολόγηση από ομότιμους (peer reviewed):	Ναι
Κάτοχος πνευματικών δικαιωμάτων:	© 2018 The Author(s).
Όροι και προϋποθέσεις δικαιωμάτων:	All Open Access, Gold, Green
Σημειώσεις:	Flight Attendant Medical Research Institute, FAMRI; Kræftens Bekæmpelse, DCS: R124-A7785-15-S2, R167-A11068-17-S2; Natur og Univers, Det Frie Forskningsråd, FNU, DFF: DFF-7016-00313; Horizon 2020 Framework Programme, H2020: 722729; Danmarks Grundforskningsfond, DNRF: DNRF125; Vetenskapsrådet, VR; Horizon 2020; Novo Nordisk Fonden, NNF: NNF14CC0001, NNF15OC0016584. This work received funding from The Scientific Committee (KBVU) of the Danish Cancer Society (Grants No R124-A7785-15-S2 and R167-A11068-17-S2), the Danish Cancer Society, The Danish Council for Independent Research (grant No DFF-7016-00313), the Danish National Research Foundation (DNRF125, project CARD), the Novo Nordisk Foundation (grants No NNF15OC0016584 and No NNF14CC0001), the Flight Attendant Medical Research Institute (Florida, USA), the “SYNTRAIN” ITN Horizon 2020 grant No 722729, the Swedish Research Council, and Cancerfonden Sweden.
Εμφανίζεται στις συλλογές:	Ινστιτούτο Χημικής Βιολογίας - Επιστημονικό έργο