APOBEC3A induces DNA gaps through PRIMPOL and confers gap-associated therapeutic vulnerability DOI Creative Commons
Ajinkya S. Kawale, Xiaojuan Ran, Parasvi S. Patel

et al.

Science Advances, Journal Year: 2024, Volume and Issue: 10(3)

Published: Jan. 19, 2024

Mutation signatures associated with apolipoprotein B mRNA editing catalytic polypeptide-like 3A/B (APOBEC3A/B) cytidine deaminases are prevalent across cancers, implying their roles as mutagenic drivers during tumorigenesis and tumor evolution. APOBEC3A (A3A) expression induces DNA replication stress increases the cellular dependency on ataxia telangiectasia Rad3-related (ATR) kinase for survival. Nonetheless, how A3A remains unclear. We show that without slowing forks. find single-stranded (ssDNA) gaps through PrimPol-mediated repriming. A3A-induced ssDNA repaired by multiple pathways involving ATR, RAD51, translesion synthesis. Both ATR inhibition trapping of poly(ADP-ribose) polymerase (PARP) PARP inhibitor impair repair gaps, preferentially killing A3A-expressing cells. When used in combination, inhibitors selectively kill cells synergistically a manner dependent PrimPol-generated gaps. Thus, arises from which confer therapeutic vulnerability to gap-targeted inhibitors.

Language: Английский

Mechanisms of APOBEC3 mutagenesis in human cancer cells DOI Creative Commons
Mia Petljak, Alexandra Dananberg, Kevan Chu

et al.

Nature, Journal Year: 2022, Volume and Issue: 607(7920), P. 799 - 807

Published: July 20, 2022

The APOBEC3 family of cytosine deaminases has been implicated in some the most prevalent mutational signatures cancer1-3. However, a causal link between endogenous enzymes and human cancer genomes not established, leaving mechanisms mutagenesis poorly understood. Here, to investigate mutagenesis, we deleted genes from cell lines that naturally generate APOBEC3-associated over time4. Analysis non-clustered clustered across whole-genome sequences 251 breast, bladder lymphoma line clones revealed APOBEC3A deletion diminished signatures. Deletion both APOBEC3B further decreased mutation burdens, without eliminating them. increased protein levels, activity APOBEC3A-mediated lines. uracil glycosylase UNG was required for APOBEC3-mediated transversions, whereas loss translesion polymerase REV1 overall burdens. Together, these data represent direct evidence cells. Our results identify as main driver mutations, indicate can restrain APOBEC3A-dependent while contributing its own smaller burdens dissect translate activities into distinct

Language: Английский

Citations

184
St. Jude Cloud: A Pediatric Cancer Genomic Data-Sharing Ecosystem DOI Open Access
Clay McLeod, Alexander M. Gout, Xin Zhou

et al.

Cancer Discovery, Journal Year: 2021, Volume and Issue: 11(5), P. 1082 - 1099

Published: Jan. 6, 2021

Abstract Effective data sharing is key to accelerating research improve diagnostic precision, treatment efficacy, and long-term survival in pediatric cancer other childhood catastrophic diseases. We present St. Jude Cloud (https://www.stjude.cloud), a cloud-based data-sharing ecosystem for accessing, analyzing, visualizing genomic from >10,000 patients with survivors, >800 sickle cell patients. Harmonized totaling 1.25 petabytes are freely available, including 12,104 whole genomes, 7,697 exomes, 2,202 transcriptomes. The resource expanding rapidly, regular uploads Jude's prospective clinical genomics programs. Three interconnected apps within the ecosystem—Genomics Platform, Pediatric Cancer Knowledgebase, Visualization Community—enable simultaneously performing advanced analysis cloud enhancing knowledgebase. demonstrate value of through use cases that classify 135 subtypes by gene expression profiling map mutational signatures across 35 subtypes. Significance: To advance cancer, we developed Cloud, accessing >1.2 raw innovative workflows, integrative multiomics visualizations, knowledgebase published contributed global community. This article highlighted In Issue feature, p. 995

Language: Английский

Citations

173
ER-directed TREX1 limits cGAS activation at micronuclei DOI
Lisa Mohr, Eléonore Toufektchan, Patrick von Morgen

et al.

Molecular Cell, Journal Year: 2021, Volume and Issue: 81(4), P. 724 - 738.e9

Published: Jan. 20, 2021

Language: Английский

Citations

160
Genomic and evolutionary classification of lung cancer in never smokers DOI
Tongwu Zhang, Philippe Joubert, Naser Ansari‐Pour

et al.

Nature Genetics, Journal Year: 2021, Volume and Issue: 53(9), P. 1348 - 1359

Published: Sept. 1, 2021

Language: Английский

Citations

156
APOBEC: A molecular driver in cervical cancer pathogenesis DOI Open Access

Sundaramoorthy Revathidevi,

Avaniyapuram Kannan Murugan, Hirofumi Nakaoka

et al.

Cancer Letters, Journal Year: 2020, Volume and Issue: 496, P. 104 - 116

Published: Oct. 7, 2020

Language: Английский

Citations

151
Somatic genomic changes in single Alzheimer’s disease neurons DOI
Michael B. Miller, August Yue Huang, Jun‐Ho Kim

et al.

Nature, Journal Year: 2022, Volume and Issue: 604(7907), P. 714 - 722

Published: April 20, 2022

Language: Английский

Citations

151
Mapping clustered mutations in cancer reveals APOBEC3 mutagenesis of ecDNA DOI Creative Commons
Erik N. Bergstrom, Jens Luebeck, Mia Petljak

et al.

Nature, Journal Year: 2022, Volume and Issue: 602(7897), P. 510 - 517

Published: Feb. 9, 2022

Clustered somatic mutations are common in cancer genomes and previous analyses reveal several types of clustered single-base substitutions, which include doublet- multi-base substitutions

Language: Английский

Citations

119
Recurrence mechanisms of non-muscle-invasive bladder cancer — a clinical perspective DOI
Jeremy Yuen‐Chun Teoh, Ashish M. Kamat, Peter C. Black

et al.

Nature Reviews Urology, Journal Year: 2022, Volume and Issue: 19(5), P. 280 - 294

Published: March 31, 2022

Language: Английский

Citations

111
Temozolomide Treatment Alters Mismatch Repair and Boosts Mutational Burden in Tumor and Blood of Colorectal Cancer Patients DOI Creative Commons
Giovanni Crisafulli, Andrea Sartore‐Bianchi, Luca Lazzari

et al.

Cancer Discovery, Journal Year: 2022, Volume and Issue: 12(7), P. 1656 - 1675

Published: May 6, 2022

The majority of metastatic colorectal cancers (mCRC) are mismatch repair (MMR) proficient and unresponsive to immunotherapy, whereas MMR-deficient (MMRd) tumors often respond immune-checkpoint blockade. We previously reported that the treatment cancer preclinical models with temozolomide (TMZ) leads MMR deficiency, increased tumor mutational burden (TMB), sensitization immunotherapy. To clinically translate these findings, we designed ARETHUSA clinical trial whereby O6-methylguanine-DNA-methyltransferase (MGMT)-deficient, MMR-proficient, RAS-mutant mCRC patients received priming therapy TMZ. Analysis tissue biopsies circulating DNA (ctDNA) revealed emergence a distinct signature TMB after TMZ treatment. Multiple alterations in nucleotide context favored by emerged genes, p.T1219I MSH6 variant was detected ctDNA 94% (16/17) cases. A subset whose displayed mutation, signature, achieved disease stabilization upon pembrolizumab MMR-proficient mCRCs provide proof concept inactivation genes can be pharmacologically molecularly monitored blood mCRC. This strategy deserves additional evaluation no longer responsive standard-of-care treatments. See related commentary Willis Overman, p. 1612. article is highlighted In Issue feature, 1599.

Language: Английский

Citations

87
Single-cell analysis of somatic mutations in human bronchial epithelial cells in relation to aging and smoking DOI
Zhenqiu Huang, Shixiang Sun, Moonsook Lee

et al.

Nature Genetics, Journal Year: 2022, Volume and Issue: 54(4), P. 492 - 498

Published: April 1, 2022

Language: Английский

Citations

83