Clamping down on mammalian meiosis

Abstract

T he RAD9A-RAD1-HUS1 (9-1-1) complex is a PCNA-like heterotrimeric clamp that binds damaged DNA to promote cell cycle checkpoint signaling and DNA repair. While various 9-1-1 functions in mammalian somatic cells have been established, mounting evidence from lower eukaryotes predicts critical roles in meiotic germ cells as well. This was investigated in 2 recent studies in which the 9-1-1 complex was disrupted specifically in the mouse male germline through conditional deletion of Rad9a or Hus1. Loss of these clamp subunits led to severely impaired fertility and meiotic defects, including faulty DNA double-strand break repair. While 9-1-1 is critical for ATR kinase activation in somatic cells, these studies did not reveal major defects in ATR checkpoint pathway signaling in meiotic cells. Intriguingly, this new work identified separable roles for 9-1-1 subunits, namely RAD9A-and HUS1-independent roles for RAD1. Based on these studies and the high-level expression of the paralogous proteins RAD9B and HUS1B in testis, we propose a model in which multiple alternative 9-1-1 clamps function during mammalian meiosis to ensure genome maintenance in the germline.

Functional compartmentalization of Rad9 and Hus1 reveals diverse assembly of the 9‐1‐1 complex components during the DNA damage response in Leishmania

“…In contrast with PCNA, the heterotrimeric nature of the eukaryotic 9-1-1 clamp adds complexity to its regulation and might expand its range of functions. In mammals and yeast, the functional diversification of the 9-1-1 clamp results from the appearance of Hus1 and Rad9 paralogs and isoforms (Lyndaker et al, 2013b). As an example, the formation of noncanonical complexes involving Rad9B, Rad1 and Hus1B has been suggested as an essential factor for proper completion of mammalian meiosis (Lyndaker et al, 2013b).…”

“…In mammals and yeast, the functional diversification of the 9-1-1 clamp results from the appearance of Hus1 and Rad9 paralogs and isoforms (Lyndaker et al, 2013b). As an example, the formation of noncanonical complexes involving Rad9B, Rad1 and Hus1B has been suggested as an essential factor for proper completion of mammalian meiosis (Lyndaker et al, 2013b). It has also been reported that the human paralog Rad9B seems to be involved not only in the G1/S transition, but also in the response to nucleolar stress (Perez-Castro and Freire, 2012).…”

“…It is also becoming clear that functional diversification of 9-1-1 has been further intensified during evolution by the appearance of variants of Rad9 and Hus1. In mammals, the Rad9B paralog seems to be involved in cell cycle progression in the G1/S transition and also in the regulation of meiosis (Perez-Castro and Freire, 2012, Lyndaker et al, 2013a, 2013b. In yeast, a Rad9 isoform participates in the response to heat shock stress in a 9-1-1 independent manner (Janes et al, 2012).…”

Whole genome sequencing identifies allelic ratio distortion in sperm involving genes related to spermatogenesis in a swine model

“…The first group of genes were involved in the formation and repair of double-strand breaks during meiosis, which result in homologous recombination. This group included well-described genes such as BRCA2 , 41 EME1 , 42 GEN1 , 43 HSF1 , 44 MEI1 , 45 , 46 RAD51B , 47 RAD9B , a paralog of RAD9A , which is involved in DNA double-strand break repair during meiosis in mice, 48 MSH2 49 and PMS2 . 50 …”

The Role of Artificial Intelligence in the Diagnosis and Prognosis of Renal Cell Tumors

“…The HUS1B (Checkpoint protein HUS1B) gene forms a complex with Rad9 and Rad1 which are involved in response to damaged DNA, triggering cell cycle checkpoint signaling and DNA repair mechanisms [ 44 ]. CACNA1D (Voltage-dependent L-type calcium channel subunit alpha-1D) is lowly expressed in RCC [ 45 ], and the expression level of CASP9 (Caspase-9) is altered in RCC by rs12124078 SNP [ 46 ], while CTSG (Cathepsin G) inhibition enhances apoptosis in human renal carcinoma (Caki) cells [ 47 ].…”