RT Journal Article
SR Electronic
T1 ATR is a multifunctional regulator of male mouse meiosis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 172106
DO 10.1101/172106
A1 Alexander Widger
A1 Shantha K Mahadevaiah
A1 Julian Lange
A1 Elias Ellnati
A1 Jasmin Zohren
A1 Takayuki Hirota
A1 Marcello Stanzione
A1 Obah Ojarikre
A1 Valdone Maciulyte
A1 Dirk de Rooij
A1 Attila Tóth
A1 Scott Keeney
A1 James MA Turner
YR 2017
UL http://biorxiv.org/content/early/2017/09/15/172106.abstract
AB Meiotic cells undergo genetic exchange between homologous chromosomes through programmed DNA double-strand break (DSB) formation, recombination and synapsis1, 2. In mice, the DNA damage-regulated phosphatidylinositol-3-kinase-like kinase (PIKK) ATM regulates all of these processes3-6. However, the meiotic functions of another major PIKK, ATR, have remained elusive, because germ line-specific depletion of this kinase is challenging. Using an efficient conditional strategy, we uncover roles for ATR in male mouse prophase I progression. Deletion of ATR causes chromosome axis fragmentation and germ cell elimination at mid pachynema. ATR is required for homologous synapsis, in a manner genetically dissociable from DSB formation. In addition, ATR regulates loading of recombinases RAD51 and DMC1 to DSBs and maintenance of recombination foci on synapsed and asynapsed chromosomes. Mid pachytene spermatocyte elimination in ATR deficient mice cannot be rescued by deletion of ATM and the third DNA damage-regulated PIKK, PRKDC, consistent with the existence of a PIKK-independent surveillance mechanism in the mammalian germ line. Our studies identify ATR as a multifunctional regulator of mouse meiosis.