SAMHD1 enhances immunoglobulin hypermutation by promoting transversion mutation

SAMHD1 enhances immunoglobulin hypermutation by promoting transversion mutation.

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1073/pnas.1719771115
Journal or Publication Title: Proceedings of the National Academy of Sciences
Volume: 115
Number: 19
Page Range: pp. 4921-4926
Date: 2018
Divisions: Immune Imaging
Depositing User: General Admin
Identification Number: 10.1073/pnas.1719771115
ISSN: 0027-8424
Date Deposited: 03 Jan 2021 22:38
Abstract:

Activation-induced deaminase (AID) initiates hypermutation of Ig genes in activated B cells by converting C:G into U:G base pairs. G1-phase variants of uracil base excision repair (BER) and mismatch repair (MMR) then deploy translesion polymerases including REV1 and Pol η, which exacerbates mutation. dNTP paucity may contribute to hypermutation, because dNTP levels are reduced in G1 phase to inhibit viral replication. To derestrict G1-phase dNTP supply, we CRISPR-inactivated SAMHD1 (which degrades dNTPs) in germinal center B cells. Samhd1 inactivation increased B cell virus susceptibility, increased transition mutations at C:G base pairs, and substantially decreased transversion mutations at A:T and C:G base pairs in both strands. We conclude that SAMHD1's restriction of dNTP supply enhances AID's mutagenicity and that the evolution of Ig hypermutation included the repurposing of antiviral mechanisms based on dNTP starvation.

Creators:
Creators
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Thientosapol, Eddy Sanchai
UNSPECIFIED
Bosnjak, Daniel
UNSPECIFIED
Durack, Timothy
UNSPECIFIED
Stevanovski, Igor
UNSPECIFIED
van Geldermalsen, Michelle
UNSPECIFIED
Holst, Jeff
UNSPECIFIED
Jahan, Zeenat
UNSPECIFIED
Shepard, Caitlin
UNSPECIFIED
Weninger, Wolfgang
UNSPECIFIED
Kim, Baek
UNSPECIFIED
Brink, Robert
UNSPECIFIED
Jolly, Christopher J.
UNSPECIFIED
Last Modified: 03 Jan 2021 22:38
URI: https://eprints.centenary.org.au/id/eprint/536

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