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Molecular basis for DNA repair synthesis on short gaps by mycobacterial Primase-Polymerase C

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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 Doherty
Cells 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 Communications

ISSN

2041-1723

Publisher

Springer Nature

Volume

11

Article number

a4196

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2020-08-25

First Open Access (FOA) Date

2020-08-25

First Compliant Deposit (FCD) Date

2020-08-24

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