Matches in SemOpenAlex for { <https://semopenalex.org/work/W2912662745> ?p ?o ?g. }
- W2912662745 abstract "Disruptor of telomeric silencing 1-like (DOT1L) is a non-SET domain containing methyltransferase known to catalyze mono-, di-, and tri-methylation of histone 3 on lysine 79 (H3K79me). DOT1L-mediated H3K79me has been implicated in chromatin-associated functions including gene transcription, heterochromatin formation, and DNA repair. Recent studies have uncovered a role for DOT1L in the initiation and progression of leukemia and other solid tumors. The development and availability of small molecule inhibitors of DOT1L may provide new and unique therapeutic options for certain types or subgroups of cancer. In this study, we examined the role of DOT1L in DNA double-strand break (DSB) response and repair by depleting DOT1L using siRNA or inhibiting its methyltransferase activity using small molecule inhibitors in colorectal cancer cells. Cells were treated with different agents to induce DNA damage in DOT1L-depleted or -inhibited cells and analyzed for DNA repair efficiency and survival. Further, rectal cancer patient samples were analyzed for H3K79me3 levels in order to determine whether it may serve as a potential marker for personalized therapy. Our results indicate that DOT1L is required for a proper DNA damage response following DNA double-strand breaks by regulating the phosphorylation of the variant histone H2AX (γH2AX) and repair via homologous recombination (HR). Importantly, we show that small molecule inhibitors of DOT1L combined with chemotherapeutic agents that are used to treat colorectal cancers show additive effects. Furthermore, examination of H3K79me3 levels in rectal cancer patients demonstrates that lower levels correlate with a poorer prognosis. In this study, we conclude that DOT1L plays an important role in an early DNA damage response and repair of DNA double-strand breaks via the HR pathway. Moreover, DOT1L inhibition leads to increased sensitivity to chemotherapeutic agents and PARP inhibition, which further highlights its potential clinical utility. Our results further suggest that H3K79me3 can be useful as a predictive and or prognostic marker for rectal cancer patients." @default.
- W2912662745 created "2019-02-21" @default.
- W2912662745 creator A5001444848 @default.
- W2912662745 creator A5003363881 @default.
- W2912662745 creator A5010964383 @default.
- W2912662745 creator A5013651038 @default.
- W2912662745 creator A5022506319 @default.
- W2912662745 creator A5023489930 @default.
- W2912662745 creator A5026778626 @default.
- W2912662745 creator A5027834625 @default.
- W2912662745 creator A5036777296 @default.
- W2912662745 creator A5038033372 @default.
- W2912662745 creator A5041792287 @default.
- W2912662745 creator A5044102221 @default.
- W2912662745 creator A5059210191 @default.
- W2912662745 creator A5073922536 @default.
- W2912662745 creator A5077513597 @default.
- W2912662745 creator A5080197054 @default.
- W2912662745 date "2019-01-07" @default.
- W2912662745 modified "2023-10-05" @default.
- W2912662745 title "The histone methyltransferase DOT1L is required for proper DNA damage response, DNA repair, and modulates chemotherapy responsiveness" @default.
- W2912662745 cites W1500422623 @default.
- W2912662745 cites W1538419182 @default.
- W2912662745 cites W1934094702 @default.
- W2912662745 cites W1969503475 @default.
- W2912662745 cites W1976385056 @default.
- W2912662745 cites W1977729188 @default.
- W2912662745 cites W1979385111 @default.
- W2912662745 cites W1984046947 @default.
- W2912662745 cites W1997707847 @default.
- W2912662745 cites W2009007206 @default.
- W2912662745 cites W2033172828 @default.
- W2912662745 cites W2035638429 @default.
- W2912662745 cites W2064721421 @default.
- W2912662745 cites W2069918359 @default.
- W2912662745 cites W2072007776 @default.
- W2912662745 cites W2077892030 @default.
- W2912662745 cites W2091208410 @default.
- W2912662745 cites W2094498537 @default.
- W2912662745 cites W2094646262 @default.
- W2912662745 cites W2095692554 @default.
- W2912662745 cites W2100197820 @default.
- W2912662745 cites W2103233056 @default.
- W2912662745 cites W2104954848 @default.
- W2912662745 cites W2116860088 @default.
- W2912662745 cites W2122554512 @default.
- W2912662745 cites W2128447158 @default.
- W2912662745 cites W2130257910 @default.
- W2912662745 cites W2156465196 @default.
- W2912662745 cites W2235523093 @default.
- W2912662745 cites W2314927739 @default.
- W2912662745 cites W2511945448 @default.
- W2912662745 cites W2749716015 @default.
- W2912662745 cites W2784108659 @default.
- W2912662745 cites W2793212766 @default.
- W2912662745 cites W2802129476 @default.
- W2912662745 cites W2806904888 @default.
- W2912662745 doi "https://doi.org/10.1186/s13148-018-0601-1" @default.
- W2912662745 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6323691" @default.
- W2912662745 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30616689" @default.
- W2912662745 hasPublicationYear "2019" @default.
- W2912662745 type Work @default.
- W2912662745 sameAs 2912662745 @default.
- W2912662745 citedByCount "39" @default.
- W2912662745 countsByYear W29126627452019 @default.
- W2912662745 countsByYear W29126627452020 @default.
- W2912662745 countsByYear W29126627452021 @default.
- W2912662745 countsByYear W29126627452022 @default.
- W2912662745 countsByYear W29126627452023 @default.
- W2912662745 crossrefType "journal-article" @default.
- W2912662745 hasAuthorship W2912662745A5001444848 @default.
- W2912662745 hasAuthorship W2912662745A5003363881 @default.
- W2912662745 hasAuthorship W2912662745A5010964383 @default.
- W2912662745 hasAuthorship W2912662745A5013651038 @default.
- W2912662745 hasAuthorship W2912662745A5022506319 @default.
- W2912662745 hasAuthorship W2912662745A5023489930 @default.
- W2912662745 hasAuthorship W2912662745A5026778626 @default.
- W2912662745 hasAuthorship W2912662745A5027834625 @default.
- W2912662745 hasAuthorship W2912662745A5036777296 @default.
- W2912662745 hasAuthorship W2912662745A5038033372 @default.
- W2912662745 hasAuthorship W2912662745A5041792287 @default.
- W2912662745 hasAuthorship W2912662745A5044102221 @default.
- W2912662745 hasAuthorship W2912662745A5059210191 @default.
- W2912662745 hasAuthorship W2912662745A5073922536 @default.
- W2912662745 hasAuthorship W2912662745A5077513597 @default.
- W2912662745 hasAuthorship W2912662745A5080197054 @default.
- W2912662745 hasBestOaLocation W29126627451 @default.
- W2912662745 hasConcept C102744134 @default.
- W2912662745 hasConcept C104317684 @default.
- W2912662745 hasConcept C114691636 @default.
- W2912662745 hasConcept C121912465 @default.
- W2912662745 hasConcept C134935766 @default.
- W2912662745 hasConcept C143425029 @default.
- W2912662745 hasConcept C150194340 @default.
- W2912662745 hasConcept C150425827 @default.
- W2912662745 hasConcept C190727270 @default.
- W2912662745 hasConcept C33288867 @default.
- W2912662745 hasConcept C41091548 @default.
- W2912662745 hasConcept C502942594 @default.
- W2912662745 hasConcept C54355233 @default.