The KRAB Domain of ZNF10 Guides the Identification of Specific Amino Acids That Transform the Ancestral KRAB-A-Related Domain Present in Human PRDM9 into a Canonical Modern KRAB-A Domain.
PRDM9 expression in tumors is significantly higher than in healthy neighboring tissues. Aberrant expression of PRDM9 is associated with genomic instability in cancers.
Recent findings have highlighted an unexpected molecular control of the distribution of meiotic double-strand breaks (DSBs) in mammals by a rapidly evolving gene in trans PR-domain-containing 9 (PRDM9) and specific DNA sequence motifs in cis
PRDM9 activity leads to the erosion of its own binding sites and the rapid evolution of its DNA-binding domain. PRDM9 may also contribute to reproductive isolation as it is involved in hybrid sterility potentially due to a reduction of its activity in specific heterozygous contexts. (review)
Finally the authors demonstrate that in addition to binding DNA PRDM9's zinc fingers also mediate its multimerization and they show that a pair of highly diverged alleles preferentially form homo-multimers.
The most common genetic variant of PRDM9 is allele A (PRDM9a) which contains 13 Cys2-His2 zinc fingers (ZF); the second-most common variant among African populations is allele C (PRDM9c) which contains 14 Cys2-His2 ZF. Data suggest that Ser764 in ZF9 allows PRDM9c to accommodate a variable base whereas PRDM9a Arg764 recognizes a conserved guanine.
subspecies-specific degradation of PRDM9 binding sites by meiotic drive which steadily increases asymmetric PRDM9 binding has impacts beyond simply changing hotspot positions and strongly support a direct involvement in hybrid infertility
PRDM9 protein variants form functional heteromeric complexes which can bind hotspots sequences. When a heteromeric complex binds at a hotspot of one PRDM9 variant the other PRDM9 variant which would otherwise not bind methylates hotspot nucleosomes
Alignment of Neandertal and Denisovan sequences suggests that PRDM9 in archaic hominins was closely related to present-day human alleles that are rare and specific to African populations.
Overexpression of PRDM9 in HEK293 cells also resulted in a significant increase in trimethylated H3K36 and H3K4 further confirming our in vitro observations
We identified PRDM9 as being associated with unusual recombination patterns and discovered a substantial excess of rare allelic forms of PRDM9 in two independent acute lymphoblastic leukemia cohorts.
observed a increased frequency of PRDM9 variants in parents who transmitted de novo 7q11.23 deletions to their offspring. These data suggest that certain PRDM9 alleles may be associated with an increased susceptibility to recurrent 7q11.23 microdeletions
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