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Molecular basis for DNA repair synthesis on short gaps by mycobacterial Primase-Polymerase C
Version 2 2023-06-07, 08:56
Version 1 2023-06-07, 07:47
journal contribution
posted on 2023-06-07, 08:56 authored by Nigel Brissett, Katerina Zabrady, Przemyslaw Plocinski, Julie Bianchi, Malgorzata Korycka-Machala, Anna Brzostek, Jaroslaw Dziadek, Aidan DohertyAidan DohertyCells utilise specialized polymerases from the Primase-Polymerase (Prim-Pol) superfamily to maintain genome stability. Prim-Pol’s function in genome maintenance pathways including replication, repair and damage tolerance. Mycobacteria contain multiple Prim-Pols required for lesion repair, including Prim-PolC that performs short gap repair synthesis during excision repair. To understand the molecular basis of Prim-PolC’s gap recognition and synthesis activities, we elucidated crystal structures of pre- and post-catalytic complexes bound to gapped DNA substrates. These intermediates explain its binding preference for short gaps and reveal a distinctive modus operandi called Synthesis-dependent Template Displacement (STD). This mechanism enables Prim-PolC to couple primer extension with template base dislocation, ensuring that the unpaired templating bases in the gap are ushered into the active site in an ordered manner. Insights provided by these structures establishes the molecular basis of Prim-PolC’s gap recognition and extension activities, while also illuminating the mechanisms of primer extension utilised by closely related Prim-Pols.
Funding
Understanding the role of PrimPol in damage tolerance during genome replication in eukaryotic cells; G1621; BBSRC-BIOTECHNOLOGY & BIOLOGICAL SCIENCES RESEARCH COUNCIL
Elucidating the mechanism of non-canonical DNA mismatch repair in mycobacteria; G2058; BBSRC-BIOTECHNOLOGY & BIOLOGICAL SCIENCES RESEARCH COUNCIL; BB/P007031/1
Molecular and cellular mechanisms utilized by Primase-Polymerase centric DNA repair pathways during stationary phase in mycobacteria; G2705; BBSRC-BIOTECHNOLOGY & BIOLOGICAL SCIENCES RESEARCH COUNCIL; BB/S008691/1
History
Publication status
- Published
File Version
- Published version
Journal
Nature CommunicationsISSN
2041-1723Publisher
Springer NatureExternal DOI
Volume
11Article number
a4196Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2020-08-25First Open Access (FOA) Date
2020-08-25First Compliant Deposit (FCD) Date
2020-08-24Usage metrics
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