Understanding oncogenicity of cancer driver genes and mutations in the cancer genomics era

Porta-Pardo, Eduard; Valencia, Alfonso; Godzik, Adam

doi:10.1002/1873-3468.13781

Cited by 34 publications

(23 citation statements)

References 104 publications

(119 reference statements)

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“…April 2020; https://cancer.sanger.ac.uk/cosmic) 14 lists 223 and 652 somatic nonsense/missense/frame shift mutations in the ascc2 and ascc3 genes, respectively (822 and 2197 tested human cancer samples, respectively). As cancers can be caused by the acquisition of somatic mutations 15 , the large number of somatic ascc2 and ascc3 mutations observed in cancer samples might be linked to the roles of ASCC/AlkBH3 in sensing and repairing alkylated DNA lesions. Moreover, chemotherapy is one of the most widely used cancer treatments and causes various DNA lesions, including alkylation damage 16 .…”

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The interaction of DNA repair factors ASCC2 and ASCC3 is affected by somatic cancer mutations

et al. 2020

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The ASCC3 subunit of the activating signal co-integrator complex is a dual-cassette Ski2-like nucleic acid helicase that provides single-stranded DNA for alkylation damage repair by the α-ketoglutarate-dependent dioxygenase AlkBH3. Other ASCC components integrate ASCC3/AlkBH3 into a complex DNA repair pathway. We mapped and structurally analyzed interacting ASCC2 and ASCC3 regions. The ASCC3 fragment comprises a central helical domain and terminal, extended arms that clasp the compact ASCC2 unit. ASCC2–ASCC3 interfaces are evolutionarily highly conserved and comprise a large number of residues affected by somatic cancer mutations. We quantified contributions of protein regions to the ASCC2–ASCC3 interaction, observing that changes found in cancers lead to reduced ASCC2–ASCC3 affinity. Functional dissection of ASCC3 revealed similar organization and regulation as in the spliceosomal RNA helicase Brr2. Our results delineate functional regions in an important DNA repair complex and suggest possible molecular disease principles.

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The interaction of DNA repair factors ASCC2 and ASCC3 is affected by somatic cancer mutations

et al. 2020

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The interaction of DNA repair factors ASCC2 and ASCC3 is affected by somatic cancer mutations

Jia

Absmeier

Holton

et al. 2020

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23The ASCC3 subunit of the activating signal co-integrator complex is a dual-cassette like nucleic acid helicase that provides single-stranded DNA for alkylation damage repair by 25 the α-ketoglutarate-dependent dioxygenase, AlkBH3. Other ASCC components integrate 26 ASCC3/AlkBH3 into a complex DNA repair pathway. We mapped and structurally analyzed 27 interacting ASCC2 and ASCC3 regions. The ASCC3 fragment comprises a central helical 28 domain and terminal, extended arms that clasp the compact ASCC2 unit. ASCC2-ASCC3 29 interfaces are evolutionarily highly conserved and comprise a large number of residues 30 affected by somatic cancer mutations. We quantified contributions of protein regions to the 31 ASCC2-ASCC3 interaction, observing that changes found in cancers lead to reduced ASCC2-32 ASCC3 affinity. Functional dissection of ASCC3 revealed similar organization and regulation 33 as in the spliceosomal RNA helicase, Brr2. Our results delineate functional regions in an 34 important DNA repair complex and suggest possible molecular disease principles. 35 36 Main 37 The human genome is constantly under assault by endogenous or exogenous DNA 38 damaging agents. To ward off these insults, cells have evolved systems to recognize DNA 39 damage, signal its presence and initiate repair processes. 1 Among the diverse repair 40 mechanisms, direct DNA repair processes represent efficient means to revert chemical 41 changes to DNA and involve enzymes such as photolyases, alkyl-transferases or 42 dioxygenases. 2,3 Escherichia coli α-ketoglutarate-dependent dioxygenase, AlkB, homologs 43 (AlkBH's) are one class of important DNA repair factors that reverse N-alkyl lesions. 4 Among 44 3 the nine identified AlkBH enzymes in human, AlkBH2 and AlkBH3 de-alkylate 1-methyl 45 adenosine and 3-methyl cytosine. 5,6 46Several lines of evidence implicate the human activating signal co-integrator complex 47 (ASCC) in AlkBH3-mediated DNA repair. ASCC is composed of four subunits, ASCC1, ASCC2, 48 ASCC3 and ASC1/TRIP4. 7,8 ASCC3 is the largest subunit of ASCC and was characterized as 49 a DNA helicase that unwinds DNA by translocating on one strand in 3'-to-5' direction. 8 The 50 enzyme is thought to provide single-stranded DNA as a substrate for de-alkylation repair by 51AlkBH3. 8 ASCC and alkylated nucleotides co-localize at nuclear foci upon alkylation damage 52 stress, dependent on a coupling of ubiquitin conjugation to ER degradation (CUE) domain in 53 ASCC2, which links DNA alkylation damage repair to upstream ubiquitin signaling via the RING 54 finger protein 113A. 9 ASCC1 is cleared from these foci upon DNA alkylation damage and 55 knockout of ASCC1 leads to loss of ASCC2 from the nuclear foci and increased cellular 56 sensitivity to alkylating insults. 10 57 Both ASCC2 and ASCC3 have been linked to various human diseases. ASCC2 is 58 upregulated in rheumatoid arthritis patients 11 , and ASCC3 is upregulated in peripheral blood 59 mononuclear cells from lung cancer patients 12,13 . A role of ASCC3 in cancer development or 60 pr...

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“…Although the widespread adoption of whole-exome sequencing and computational tools in cancer genomics has brought us to a nearly complete catalogue of cancer driver genes ( Porta-Pardo et al 2020 ), one of the most pressing questions remaining is which mutations on these genes are driver mutations, as personalized treatment hinges on its answer. Our framework, in light of its residue-resolution characterization of protein interfaces, then stands a superior approach to the prevalent gene-level statistical models.…”

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A full-proteome, interaction-specific characterization of mutational hotspots across human cancers

et al. 2021

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Rapid accumulation of cancer genomic data has led to the identification of an increasing number of mutational hotspots with uncharacterized significance. Here we present a biologically informed computational framework that characterizes the functional relevance of all 1107 published mutational hotspots identified in approximately 25,000 tumor samples across 41 cancer types in the context of a human 3D interactome network, in which the interface of each interaction is mapped at residue resolution. Hotspots reside in network hub proteins and are enriched on protein interaction interfaces, suggesting that alteration of specific protein–protein interactions is critical for the oncogenicity of many hotspot mutations. Our framework enables, for the first time, systematic identification of specific protein interactions affected by hotspot mutations at the full proteome scale. Furthermore, by constructing a hotspot-affected network that connects all hotspot-affected interactions throughout the whole-human interactome, we uncover genome-wide relationships among hotspots and implicate novel cancer proteins that do not harbor hotspot mutations themselves. Moreover, applying our network-based framework to specific cancer types identifies clinically significant hotspots that can be used for prognosis and therapy targets. Overall, we show that our framework bridges the gap between the statistical significance of mutational hotspots and their biological and clinical significance in human cancers.

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Understanding oncogenicity of cancer driver genes and mutations in the cancer genomics era

Cited by 34 publications

References 104 publications

The interaction of DNA repair factors ASCC2 and ASCC3 is affected by somatic cancer mutations

The interaction of DNA repair factors ASCC2 and ASCC3 is affected by somatic cancer mutations

The interaction of DNA repair factors ASCC2 and ASCC3 is affected by somatic cancer mutations

A full-proteome, interaction-specific characterization of mutational hotspots across human cancers

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