Mouse HORMAD1 and HORMAD2, two conserved meiotic chromosomal proteins, are depleted from synapsed chromosome axes with the help of TRIP13 AAA-ATPase.
Meiotic crossovers are produced when programmed double-strand breaks (DSBs) are repaired by recombination from homologous chromosomes (homologues). In a wide variety of organisms, meiotic HORMA-domain proteins are required to direct DSB repair towards homologues. This inter-homologue bias is required for efficient homology search, homologue alignment, and crossover formation. HORMA-domain proteins are also implicated in other processes related to crossover formation, including DSB formation, inhibition of promiscuous formation of the synaptonemal complex (SC), and the meiotic prophase checkpoint that monitors both DSB processing and SCs. We examined the behavior of two previously uncharacterized meiosis-specific mouse HORMA-domain proteins--HORMAD1 and HORMAD2--in wild-type mice and in mutants defective in DSB processing or SC formation. HORMADs are preferentially associated with unsynapsed chromosome axes throughout meiotic prophase. We observe a strong negative correlation between SC formation and presence of HORMADs on axes, and a positive correlation between the presumptive sites of high checkpoint-kinase ATR activity and hyper-accumulation of HORMADs on axes. HORMADs are not depleted from chromosomes in mutants that lack SCs. In contrast, DSB formation and DSB repair are not absolutely required for depletion of HORMADs from synapsed axes. A simple interpretation of these findings is that SC formation directly or indirectly promotes depletion of HORMADs from chromosome axes. We also find that TRIP13 protein is required for reciprocal distribution of HORMADs and the SYCP1/SC-component along chromosome axes. Similarities in mouse and budding yeast meiosis suggest that TRIP13/Pch2 proteins have a conserved role in establishing mutually exclusive HORMAD-rich and synapsed chromatin domains in both mouse and yeast. Taken together, our observations raise the possibility that involvement of meiotic HORMA-domain proteins in the regulation of homologue interactions is conserved in mammals.
Institute of Physiological Chemistry, Technische Universität Dresden, Dresden, Germany.
Lukasz
L
Wojtasz
Katrin
K
Daniel
Ignasi
I
Roig
Ewelina
E
Bolcun-Filas
Huiling
H
Xu
Verawan
V
Boonsanay
Christian R
CR
Eckmann
Howard J
HJ
Cooke
Maria
M
Jasin
Scott
S
Keeney
Michael J
MJ
McKay
Attila
A
Toth
D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D023902:Chromosome Pairing; D053903:DNA Breaks, Double-Stranded; D005260:Female; D008297:Male; D008540:Meiosis; D051379:Mice; D008810:Mice, Inbred C57BL; D013573:Synaptonemal Complex / Q000378:metabolism*
D018797:Cell Cycle Proteins; C546539:HORMAD2 protein, mouse; C506693:Nohma protein, mouse; D000251:Adenosine Triphosphatases; D000074183:ATPases Associated with Diverse Cellular Activities; C523791:Trip13 protein, mouse