A novel function for CDK2 activity at meiotic crossover sites

Abstract

Genetic diversity in offspring is induced by meiotic recombination, which is initiated between homologs at >200 sites originating from meiotic double-strand breaks (DSBs). Of this initial pool, only 1–2 DSBs per homolog pair will be designated to form meiotic crossovers (COs), where reciprocal genetic exchange occurs between parental chromosomes. Cyclin-dependent kinase 2 (CDK2) is known to localize to so-called “late recombination nodules” (LRNs) marking incipient CO sites. However, the role of CDK2 kinase activity in the process of CO formation remains uncertain. Here, we describe the phenotype of 2 Cdk2 point mutants with elevated or decreased activity, respectively. Elevated CDK2 activity was associated with increased numbers of LRN-associated proteins, including CDK2 itself and the MutL homolog 1 (MLH1) component of the MutLγ complex, but did not lead to increased numbers of COs. In contrast, reduced CDK2 activity leads to the complete absence of CO formation during meiotic prophase I. Our data suggest an important role for CDK2 in regulating MLH1 focus numbers and that the activity of this kinase is a key regulatory factor in the formation of meiotic COs.

Kinase CDK2 in Mammalian Meiotic Prophase I: Screening for Hetero- and Homomorphic Sex Chromosomes

“…These data clarify that DSB repair begins without requiring CDK2 but cannot be completed without it. The crucial input of CDK2 for meiotic crossover formation was shown recently by Palmer et al [12]. To date CDK2 is considered to play an essential role in chromosome synapsis, meiotic recombination, and formation of the sex body (special chromatin-modified domain of the male sex chromosomes at the periphery of the nucleus) during the first meiotic prophase.…”

“…The study of CDK2 manifestation and function in meiotic progression has been conducted only in laboratory mice [ 9 , 10 , 12 , 19 ]. In this case, the analysis of such a multifunctional molecule as CDK2 on other animals can be promising.…”

Phospho-Regulation of Meiotic Prophase

“…In mice, CDK2 localizes to crossover sites ( Ashley et al, 2001 ) and is required for completion of DSB repair ( Viera et al, 2009 ). In hyperactive CDK2 mutants, the number of chromosomal foci of MHL1, a subunit of the pro-crossover MutLγ complex, increases although the number of crossovers does not change ( Palmer et al, 2020 ). On the other hand, reduction of CDK2 activity blocks formation of crossovers ( Palmer et al, 2020 ).…”

“…In hyperactive CDK2 mutants, the number of chromosomal foci of MHL1, a subunit of the pro-crossover MutLγ complex, increases although the number of crossovers does not change ( Palmer et al, 2020 ). On the other hand, reduction of CDK2 activity blocks formation of crossovers ( Palmer et al, 2020 ). How and through which targets CDKs promote crossover formation in these organisms remains to be answered, but they might be acting through similar pathways.…”

“…In addition to ATR, sex chromosome silencing and XY body formation also requires CDK2 ( Viera et al, 2009 ; Wang et al, 2014 ), which localizes to the XY body in its activated T160-phosphorylated form ( Wang et al, 2014 ). The T160 phosphorylation enhances the interaction between γH2AX and CDK2 ( Wang et al, 2014 ), but it is likely needed at later stages of XY body formation and gene silencing, because γH2AX localization to XY chromatin was unaffected in the CDK2 T160A mutant ( Palmer et al, 2020 ).…”