Universität zu Köln

Reusswig, Karl-Uwe ORCID: 0000-0003-2544-4145, Bittmann, Julia, Peritore, Martina, Courtes, Mathilde, Pardo, Benjamin ORCID: 0000-0002-4760-1263, Wierer, Michael, Mann, Matthias and Pfander, Boris (2022). Unscheduled DNA replication in G1 causes genome instability and damage signatures indicative of replication collisions. Nat. Commun., 13 (1). BERLIN: NATURE PORTFOLIO. ISSN 2041-1723

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Abstract

DNA replicates once per cell cycle. Interfering with the regulation of DNA replication initiation generates genome instability through over-replication and has been linked to early stages of cancer development. Here, we engineer genetic systems in budding yeast to induce unscheduled replication in a G1-like cell cycle state. Unscheduled G1 replication initiates at canonical S-phase origins. We quantifiy the composition of replisomes in G1- and S-phase and identified firing factors, polymerase alpha, and histone supply as factors that limit replication outside S-phase. G1 replication per se does not trigger cellular checkpoints. Subsequent replication during S-phase, however, results in over-replication and leads to chromosome breaks and chromosome-wide, strand-biased occurrence of RPA-bound single-stranded DNA, indicating head-to-tail replication collisions as a key mechanism generating genome instability upon G1 replication. Low-level, sporadic induction of G1 replication induces an identical response, indicating findings from synthetic systems are applicable to naturally occurring scenarios of unscheduled replication initiation. Reusswig et al. use engineered systems to force DNA replication in the G1 phase of the cell cycle. This unscheduled G1 replication shows hallmarks of S phase replication, but leads to over-replication and DNA breaks from replication collisions.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Reusswig, Karl-Uwe UNSPECIFIED orcid.org/0000-0003-2544-4145 UNSPECIFIED Bittmann, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED Peritore, Martina UNSPECIFIED UNSPECIFIED UNSPECIFIED Courtes, Mathilde UNSPECIFIED UNSPECIFIED UNSPECIFIED Pardo, Benjamin UNSPECIFIED orcid.org/0000-0002-4760-1263 UNSPECIFIED Wierer, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Mann, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Pfander, Boris UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-689599
DOI:	10.1038/s41467-022-34379-2
Journal or Publication Title:	Nat. Commun.
Volume:	13
Number:	1
Date:	2022
Publisher:	NATURE PORTFOLIO
Place of Publication:	BERLIN
ISSN:	2041-1723
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language BREAK-INDUCED REPLICATION; INDUCIBLE DEGRON SYSTEM; CELL-CYCLE PROGRESSION; PROTEIN PHOSPHATASE 1; RE-REPLICATION; S PHASE; PHOSPHORYLATION SITES; FORK PROGRESSION; REREPLICATION; YEAST Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68959