XRN2-DDX23 Cooperation in Avoiding R-loop-induced Genomic Instability
XRN2-DDX23 Cooperation in Avoiding R-loop-induced Genomic Instability
批准号:
10654331
负责人:
Praveen Patidar
金额:
$35.56万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-08-18 至 2026-07-31
关键词:
5&apos-exoribonucleaseAutoimmune DiseasesBindingBiochemicalBiologicalBiologyCell Cycle RegulationCell SurvivalCellsCodeDNADNA DamageDNA Double Strand BreakDNA RepairDNA replication forkDataDefectDetectionDiseaseDouble Strand Break RepairEnsureEnzymesExoribonucleasesGene SilencingGenesGenetic PolymorphismGenomeGenomic InstabilityGoalsHealthHomeostasisHumanHybridsImpairmentIndividualLinkMaintenanceMalignant NeoplasmsMalignant neoplasm of lungMediatingMetabolismMolecularMutationNeurodegenerative DisordersNonhomologous DNA End JoiningNuclearPathway interactionsPoly(ADP-ribose) PolymerasesProteinsRNARNA DegradationRNA HelicaseRNA Polymerase IIRNA metabolismRegulationResearchResearch ProposalsResolutionRibosomal RNARiskRoleSingle-Stranded DNASiteSourceSpliceosomesTestingU5 Small Nuclear Ribonucleoproteinaspartylglutamateenzyme deficiencygenetic informationgenome integritygenome-wideglutamylalaninehelicaseinnovationinsightmRNA Expressionnovelnucleic acid structurepreservationpreventprogramsreplication stressresponsesensortermination factortranscription terminationtransmission process
中文摘要
项目总结
英文摘要
Project Summary
Compromised genomic integrity results in several debilitating diseases such as
neurodegenerative disorders, autoimmune diseases, and cancer. Persistent nucleic acid
structures containing RNA-DNA hybrids with a displaced single-stranded DNA (R-loops) are a
potent source of genomic instability. One of the major sources of R-loops is impaired regulation
of RNA polymerase II (RNAPII) at transcription termination sites of protein coding genes. In
humans, the 5’-3’-exoribonuclease 2 (XRN2) is essential for genome-wide timely termination of
RNAPII downstream of poly(A) sites. In essence, XRN2’s role in RNA metabolism is well
understood. However, its role in genome maintenance remains elusive and there is lack of
functional information regarding its molecular contributions in coordinating DNA repair, resolving
replication stress, and promoting cell survival. Our long-term research goal is to define the roles
of transcription termination factors including XRN2, in preventing R-loop-induced genomic
instability and identify avenues to target their vulnerabilities. For this research program, we will
primarily focus on delineating the interplay of XRN2 and DEAD (Asp-Glu-Ala-Asp) Box helicase
23 (DDX23). We recently defined the interactome of XRN2 and identified molecular links that
connect it to DNA double-strand break (DSB) repair and cell cycle control of chromosomal
replication. Our data support XRN2 and DDX23 interaction and a potential interplay of these two
enzymes in R-loop metabolism and genome maintenance. We hypothesize that XRN2-DDX23
interaction enables them to cooperatively suppress R-loop-induced genomic instability and
deficiencies of these enzymes engage central DNA damage sensor protein poly(ADP-ribose)
polymerase 1 (PARP1) to coordinate repair of DSBs emanating from impaired R-loop
homeostasis. We will pursue following specific aims to test our hypothesis; Aim 1: Determine the
biochemical basis and functional implications of XRN2 and DDX23 interaction. Aim 2: Determine
the biological significance of XRN2-DDX23 interplay in R-loop metabolism and genome
maintenance. Collectively, our studies will provide mechanistic insights into XRN2-DDX23
cooperation in avoiding R-loop-induced genomic instability, and establish potential avenues for
targeting XRN2 and DDX23 vulnerabilities.
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