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UID:1231@biology.technion.ac.il

DTSTART;TZID=Asia/Jerusalem:20240730T010000

DTEND;TZID=Asia/Jerusalem:20240730T020000

DTSTAMP:20240701T131239Z

URL:https://biology.technion.ac.il/en/seminars/phd-graduate-seminar-feras-
 machour/

SUMMARY:PhD Graduate Seminar- Feras Machour [No Categories]
DESCRIPTION:Location: Hybrid- in the Faculty Auditorium/ZOOM: https://techn
 ion.zoom.us/j/96794050334   Feras Machour\n Affiliation: \n Host:Prof. Nab
 ieh Ayoub \n Harnessing DNA replication stress to target RBM10 deficiency 
 in lung adenocarcinoma\n\nBackground and Motivation: Lung cancer has the h
 ighest mortality rate among all types of cancer worldwide. Strikingly\, th
 e RNA-binding motif protein 10 (RBM10) is the most mutated splicing fact
 or in lung adenocarcinoma (LUAD) (~9-25% of all cases). Most RBM10 cancer 
 mutations are loss-of-function\, correlating with increased tumorigenesis 
 and limiting the efficacy of current LUAD targeted therapies. Remarkably\,
  therapeutic strategies leveraging RBM10 deficiency remain unexplored\, hi
 ghlighting the urgency for innovative approaches to target RBM10 loss in L
 UAD.\nResearch Goal: Exploit the high mutation rate of RBM10 in LUAD for s
 elective eradication of RBM10-mutated LUAD tumors.\nResults: We conducted 
 a CRISPR-Cas9 synthetic lethality (SL) screen and identified ~60 RBM10 SL 
 genes\, including WEE1 kinase. WEE1 inhibition sensitized RBM10-deficient 
 LUAD cells in-vitro and in-vivo. Intriguingly\, we identified a splicing-i
 ndependent role of RBM10 in regulating DNA replication fork progression an
 d replication stress response\, which underpins RBM10-WEE1 SL. Mechanistic
 ally\, we reveal that RBM10 physically interacts with active DNA replicati
 on forks and modulates R-loop homeostasis to maintain replication fork sta
 bility.\nConclusions: Our data reveal an unexpected function of RBM10 in f
 ine-tuning DNA replication\, independent of its canonical splicing functio
 n. In a broader context\, these findings reveal an unexplored aspect of DN
 A replication regulation involving a noncanonical function of RNA splicing
  factors. Moreover\, our data provide an arsenal of therapeutic targets\, 
 such as WEE1\, that can be utilized to target RBM10-mutated LUAD tumors wi
 th immediate clinical applicability. 
LOCATION:Hybrid- in the Faculty Auditorium/ZOOM: https://technion.zoom.us/j
 /96794050334

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