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Principal Investigator: Bin Wang
Organization: UNIVERSITY OF TX MD ANDERSON CAN CTR
Fiscal Year: 2024
Award: $352,047
Funding agency: National Cancer Institute
ABSTRACT
DNA double-strand breaks (DSBs) are one of the most deleterious lesions. The cellular responses to DSBs
involve a sophisticated DNA damage response network that detects, signals and repairs the lesion; failure of
this system results in mutation, deletion and other alteration of genome and underlies many diseases. Post-
translational modifications by covalent attachment of ubiquitin to proteins, known as ubiquitination, play
important regulatory roles in the DNA damage response. Previous studies, including ours, have illustrated that,
upon DSBs detection and activation of the DNA damage response kinase ATM, Lys63-linked ubiquitination of
histone H2A/H2AX on damaged chromatin is critical in recruiting DNA damage repair proteins, including
53BP1 and BRCA1, to the damage sites. However, much remains unknown about the complexity of ubiquitin
modifications and their roles in the DNA damage response. We have discovered that Lys11-linkage–specific
ubiquitin modification occurs on damaged chromatin that regulates repression of transcription at DSBs,
revealing Lys11-linkage ubiquitin modification as a new signaling and regulatory platform in the response to
DSBs. We further showed that this modification is ATM dependent and catalyzed by RNF8 and Ube2S. In
addition, cells deficient in Lys11-linkage ubiquitin modification displayed increased sensitivity to ionizing
radiation. It indicates a model that DNA repair and transcription can be regulated by distinct linkage-specific
ubiquitin modifications at DSBs. However, it is not clear whether these two seemingly parallel linkage-specific
ubiquitination pathways are coordinated to regulate DNA repair and transcription in the cellular responses to
DSBs. The objective of this proposal is to identify the crosstalk between Lys63- and Lys11-linkage modification
on damaged chromatin and determine the underlying mechanisms through which it coordinates transcriptional
repression and DNA repair. We will pursue the following specific aims: 1) determine the crosstalk between
Lys11- and Lys63-linkage ubiquitination mediated by Cezanne to regulate DNA repair; 2) determine additional
mechanisms underlying the coordination of DNA repair and transcriptional inhibition; 3) determine the role of
Lys11- and Lys63-linkage ubiquitination at defined DSB sites in regulating DNA repair and inhibition of
transcription. Our findings should provide novel insights into the understanding of how ubiquitin modification at
DSBs is involved in signaling events to regulate inhibition of transcription and repair. Our long-term goal is to
decipher the complex DNA response network that protects genome integrity, which is essential for design of
tools and treatment to improve human health.
Terms: <53BP1><APF-1><ATM Protein><ATM Serine/Threonine Protein Kinase><ATM kinase><ATM protein kinase><ATP-Dependent Proteolysis Factor 1><Ataxia Telangiectasia Mutated><Ataxia Telangiectasia Protein><Ataxia-Telangiectasia-Mutated protein kinase><BRCA1><BRCA1 Gene Product><BRCA1 Protein><BRCA1 gene><Breast Cancer 1 Gene><Breast Cancer 1 Gene Product><Breast Cancer Type 1 Susceptibility Gene><Breast Cancer Type 1 Susceptibility Protein><Breast-Ovarian Cancer Protein><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Characteristics><Chromatin><Complex><DNA><DNA Damage><DNA Damage Repair><DNA Double Strand Break><DNA Injury><DNA Repair><DNA Repair Gene><DNA repair protein><Defect><Deoxyribonucleic Acid><Detection><Disease><Disorder><Early Onset Gene Breast Cancer 1><Early Onset Protein Breast Cancer 1><Event><Failure><Gene Down-Regulation><Gene Transcription><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Genome><Genome Stability><Genomic Stability><Goals><HMG-20><Health><Hereditary Breast Cancer 1><High Mobility Protein 20><Histone H2A><Human><Individual><Intracellular Communication and Signaling><Ionizing Electromagnetic Radiation><Ionizing radiation><L-Lysine><Lesion><Link><Lysine><Mediating><Methionine><Modeling><Modern Man><Modification><Monoubiquitination><Mutation><N-terminal><NH2-terminal><Pathway interactions><Play><Polyubiquitin><Polyubiquitination><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Production><Protein Modification><Proteins><RNA Expression><RNF53><Radiation-Ionizing Total><Reader><Regulation><Role><Signal Transduction><Signal Transduction Systems><Signaling><Site><System><TP53BP1><Transcript><Transcription><Transcription Repression><Transcriptional Repression><Translations><Ubiquitilation><Ubiquitin><Ubiquitination><Ubiquitinoylation><Unscheduled DNA Synthesis><ataxia telangiectasia mutated protein><biological signal transduction><brca 1 gene><cytotoxic><design><designing><gene repression><genome integrity><genome mutation><genomic integrity><improved><insight><ionizing output><novel><p202><p53-binding protein 1><p53BP1><pathway><poly-ubiquitin><prevent><preventing><recruit><repair><repaired><response><restriction enzyme><restriction enzymes><social role><tool><translation><ubiquination><ubiquitin conjugation>