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CATEGORIES:Seminars on Quantitative Biology @ CRUK Cambridge 
 Institute 
SUMMARY:Functional studies of genetic variation using prec
 ision genome editing - Dr Francisco J Sanchez-Rive
 ra\, Koch Institute at MIT
DTSTART;TZID=Europe/London:20240205T123000
DTEND;TZID=Europe/London:20240205T133000
UID:TALK211414AThttp://talks.cam.ac.uk
URL:http://talks.cam.ac.uk/talk/index/211414
DESCRIPTION:Functional studies of genetic variation using prec
 ision genome editing \nMany human diseases have a 
 strong association with diverse types of genetic a
 lterations. These diseases \ninclude cancer\, in w
 hich tumor genomes often harbor a complex spectrum
  of single-nucleotide alterations \nand chromosoma
 l rearrangements that can perturb gene function in
  ways that remain poorly understood. \nSome cancer
 -associated genes exhibit a tremendous degree of m
 utational heterogeneity\, which may \nimpact disea
 se initiation\, progression\, and therapy response
 s. For example\, TP53\, the most frequently \nmuta
 ted gene in cancer\, shows extensive allelic varia
 tion that leads to the generation of altered prote
 ins that \ncan produce functionally distinct pheno
 types. Whether distinct variants of TP53 and other
  genes encode \nproteins with loss-of-function\, g
 ain-of-function\, or otherwise neomorphic phenotyp
 es remains both \ncontroversial and technically ch
 allenging to assess\, particularly at the endogeno
 us level. \nPrecision genome editing technologies 
 like base editing and prime editing are uniquely s
 uited to tackle this \nproblem. Nevertheless\, dep
 loying these methods for systematic variant-functi
 on studies and disease \nmodeling in vivo has not 
 been straightforward due to lack of robust and sca
 lable platforms capable of \nassessing editing eff
 iciency and precision\, particularly at endogenous
  loci. With this goal in mind\, we \npreviously de
 veloped and applied high-throughput base editing ‘
 sensor’ approaches that link endogenous \ngenome e
 diting outcomes with synthetic DNA-based readouts 
 and cellular fitness measurements \n(PMID: 3516538
 4). Using these approaches\, we found that several
  previously uncharacterized mutant p53 \nalleles a
 re bona fide drivers of cancer cell proliferation 
 and in vivo tumor development. \nBuilding upon thi
 s work\, we recently developed new prime editing g
 uide RNA design tools and sensorbased approaches 
 that similarly couple quantitative editing outcome
 s to cellular fitness\, allowing us to \nsignifica
 ntly expand the breadth and complexity of cancer-a
 ssociated mutations that can be interrogated \nusi
 ng these technologies. We used this strategy to sc
 reen the largest collection of endogenous cancera
 ssociated TP53 variants assembled to date\, identi
 fying both known and novel alleles that impact p53
  \nfunction in mechanistically diverse ways. Intri
 guingly\, we find that certain types of endogenous
  TP53\nvariants\, particularly those in the p53 ol
 igomerization domain\, display opposite phenotypes
  in exogenous \ngene overexpression systems. These
  include disease-relevant variants found in humans
  with cancer \npredisposition syndromes that encod
 e altered proteins with unique molecular propertie
 s. \nOur results emphasize the physiological impor
 tance of gene dosage in shaping native protein sto
 ichiometry \nand protein-protein interactions\, hi
 ghlight the limitations of using exogenous overexp
 ression systems to \ninterpret pathogenic alleles\
 , and establish a computational and experimental f
 ramework for studying \ndiverse types of genetic v
 ariants in their endogenous context\, providing in
 sight into variant-function \nrelationships that c
 ould be leveraged to develop more precise therapie
 s.
LOCATION:CRUK CI Lecture Theatre
CONTACT:Kate Davenport
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