HORMAD1

HORMAD1 (HORMA domain-containing protein 1) is a germ cell–specific protein encoded by the HORMAD1 gene in mammals. It contains a HORMA domain and is evolutionarily related to other HORMA domain proteins involved in meiotic chromosome axis organization. In mice and humans, HORMAD1 is highly expressed in testes and ovaries and localizes to meiotic chromosome axes during leptotene and zygotene, associating strongly with unsynapsed chromosomal regions as part of the axis that underlies the synaptonemal complex.

During meiotic prophase I, HORMAD1 forms complexes with HORMAD2 on unsynapsed axial elements and interacts with components of the axis such as SYCP2 and SYCP3. Its association is dynamically regulated: TRIP13 (a PCH2 family ATPase) remodels HORMA domains, leading to removal of HORMAD1 from synapsed portions of chromosomes, while remaining on unsynapsed axes.

HORMAD1 is implicated in the surveillance of synapsis and recombination. It is involved in the activation of ATR-dependent signaling at unsynapsed chromatin and contributes to the meiotic checkpoint that delays progression if synapsis or DSB repair is defective, thereby helping to maintain genome integrity during meiosis.

Genetic studies in mice show that loss of HORMAD1 causes defects in synapsis and recombination, persistence of DNA damage foci, and arrest of meiosis with infertility, highlighting its essential role in meiotic chromosome axis function.