RT Journal Article
SR Electronic
T1 Germline Missense Variants in <em>CDC20</em> Result in Aberrant Mitotic Progression and Familial Cancer
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.09.13.459529
DO 10.1101/2021.09.13.459529
A1 Owen J. Chen
A1 Ester Castellsagué
A1 Mohamed Moustafa-Kamal
A1 Javad Nadaf
A1 Barbara Rivera
A1 Somayyeh Fahiminiya
A1 Yilin Wang
A1 Isabelle Gamache
A1 Caterina Pacifico
A1 Lai Jiang
A1 Jian Carrot-Zhang
A1 Leora Witkowski
A1 Albert M. Berghuis
A1 Stefan Schoenberger
A1 Dominik Schneider
A1 Susanne Bens
A1 Reiner Siebert
A1 Colin J. R. Stewart
A1 Ziguo Zhang
A1 William C. Chao
A1 Celia M.T. Greenwood
A1 David Barford
A1 Marc Tischkowitz
A1 Jacek Majewski
A1 William D. Foulkes
A1 Jose G. Teodoro
YR 2021
UL http://biorxiv.org/content/early/2021/09/14/2021.09.13.459529.abstract
AB CDC20 is a co-activator of the anaphase promoting complex/cyclosome (APC/C) and is essential for mitotic progression. APC/CCDC20 is inhibited by the spindle assembly checkpoint (SAC), which prevents premature separation of sister chromatids and aneuploidy in daughter cells. Although overexpression of CDC20 is common in many cancers, oncogenic mutations have never been identified in humans. Using whole exome sequencing, we identified heterozygous missense CDC20 variants (L151R and N331K) that segregate with cancer in two families. Characterization of these mutants showed they retain APC/C activation activity but show reduced binding to BUBR1, a component of the SAC. Expression of L151R and N331K promoted mitotic slippage in HeLa cells and primary skin fibroblasts derived from carriers. CRISPR/Cas9 was used to generate mice carrying N331K. Homozygous mice carrying N331K were non-viable, however, heterozygotes displayed accelerated oncogenicity in Myc-driven cancers. These findings highlight an unappreciated role for CDC20 variants as tumor promoting genes in humans.Competing Interest StatementThe authors have declared no competing interest.