Dissecting mutational mechanisms underpinning signatures caused by replication errors and endogenous DNA damage
Dissecting mutational mechanisms underpinning signatures caused by replication errors and endogenous DNA damage
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剖析由复制错误和内源性 DNA 损伤引起的特征的突变机制
DOI：
10.1101/2020.08.04.234245
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
S. Nik
中科院分区：
文献类型：
--
作者：
Xueqing Zou;G. Koh;A. S. Nanda;A. Degasperi;Katie Urgo;T. Roumeliotis;Chukwuma A. Agu;L. Side;G. Brice;V. Pérez;D. Rueda;Cherif Badja;Jamie Young;Celine Gomez;Wendy Bushell;R. Harris;J. Choudhary;J. Jiricny;W. Skarnes;S. Nik
Mutational signatures are imprints of pathophysiological processes arising through tumorigenesis. Here, we generate isogenic CRISPR-Cas9 knockouts (Δ) of 43 genes in human induced pluripotent stem cells, culture them in the absence of added DNA damage, and perform wholegenome sequencing of 173 daughter subclones. ΔOGG1, ΔUNG, ΔEXO1, ΔRNF168, ΔMLH1, ΔMSH2, ΔMSH6, ΔPMS1, and ΔPMS2 produce marked mutational signatures indicative of being critical mitigators of endogenous DNA changes. Detailed analyses reveal that 8-oxo-dG removal by different repair proteins is sequence-context-specific while uracil clearance is sequencecontext-independent. Signatures of mismatch repair (MMR) deficiency show components of C>A transversions due to oxidative damage, T>C and C>T transitions due to differential misincorporation by replicative polymerases, and T>A transversions for which we propose a ‘reverse template slippage’ model. ΔMLH1, ΔMSH6, and ΔMSH2 signatures are similar to each other but distinct from ΔPMS2. We validate these gene-specificities in cells from patients with Constitutive Mismatch Repair Deficiency Syndrome. Based on these experimental insights, we develop a classifier, MMRDetect, for improved clinical detection of MMR-deficient tumors.
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影响因子：
19
作者：
Ceccaldi R;Rondinelli B;D'Andrea AD
通讯作者：
D'Andrea AD
影响因子：
56.9
作者：
DRUMMOND, JT;LI, GM;MODRICH, P
通讯作者：
MODRICH, P
DOI：
10.1073/pnas.94.15.8010
发表时间：
1997-07-22
影响因子：
11.1
作者：
Radicella, JP;Dherin, C;Boiteux, S
通讯作者：
Boiteux, S
DOI：
10.1101/sqb.2000.65.127
发表时间：
2000-01-01
期刊：
COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY
影响因子：
--
作者：
Lindahl, T;Barnes, DE
通讯作者：
Barnes, DE
影响因子：
3.8
作者：
Heinen CD
通讯作者：
Heinen CD