Molecular Regulation of Cellular Senescence by MicroRNAs: Implications in Cancer and Age-Related Diseases.

Cellular senescence is a tumor suppressor response that acts as a barrier to cancer development and progression. In normal cells, diverse stimuli, including excessive mitogenic signaling, DNA damage or telomere shortening, trigger a senescence response characterized by stable growth arrest. Cellular senescence is orchestrated by tumor suppressor pathways, which have to be inactivated in order to impair the establishment of senescence and promote cancer. Consequently, by overcoming or bypassing this cellular response, cancer cells evade cell cycle checkpoint control leading to genomic instability and uncontrolled proliferation. MicroRNAs (MiRs) have emerged as essential factors contributing to or preventing cellular senescence. Here we detail the molecular mechanisms underlying the fine-tuning of cellular senescence signals by MiRs, and how the senescence response itself contributes to modulation of MiR expression, with a special focus on cancer and pathologies associated with aging.

DNA damage during meiosis induces chromatin remodeling and synaptonemal complex disassembly.

DNA damage to the germline genome must be accurately repaired to ensure transmission of intact genetic information to following generations. Meiosis presents challenges to the DNA damage response (DDR) because it universally requires changes to chromosome structure that can affect DNA repair outcomes. We report the existence of a meiotic DDR at chromosome axes that results in chromatin remodeling, synaptonemal complex disassembly, and axis separation in response to irradiation at late pachytene stages in C. elegans. The axis component HTP-3 is required for germline acquisition of H2AacK5, an axis-specific chromatin mark that is DNA damage responsive. Irradiated wild-types show reduction of H2AacK5 and axis separation that are dependent on the acetyltransferase MYS-1/TIP60. Restoration of H2AacK5 levels requires ATM-1 kinase and correlates with resynapsis. We propose that the meiotic DDR involves early chromatin remodeling at chromosome axes to dismantle structures promoting interhomolog recombination and facilitate efficient nonhomolog-based repair before pachytene exit.

HTP-3 links DSB formation with homolog pairing and crossing over during C. elegans meiosis.

Repair of the programmed meiotic double-strand breaks (DSBs) that initiate recombination must be coordinated with homolog pairing to generate crossovers capable of directing chromosome segregation. Chromosome pairing and synapsis proceed independently of recombination in worms and flies, suggesting a paradoxical lack of coregulation. Here, we find that the meiotic axis component HTP-3 links DSB formation with homolog pairing and synapsis. HTP-3 forms complexes with the DSB repair components MRE-11/RAD-50 and the meiosis-specific axis component HIM-3. Loss of htp-3 or mre-11 recapitulates meiotic phenotypes consistent with a failure to generate DSBs, suggesting that HTP-3 associates with MRE-11/RAD-50 in a complex required for meiotic DSB formation. Loss of HTP-3 eliminates HIM-3 localization to axes and HIM-3-dependent homolog alignment, synapsis, and crossing over. Our study reveals a mechanism for coupling meiotic DSB formation with homolog pairing through the essential participation of an axis component with complexes mediating both processes.

HTP-1 coordinates synaptonemal complex assembly with homolog alignment during meiosis in C. elegans.

During meiosis, the mechanisms responsible for homolog alignment, synapsis, and recombination are precisely coordinated to culminate in the formation of crossovers capable of directing accurate chromosome segregation. An outstanding question is how the cell ensures that the structural hallmark of meiosis, the synaptonemal complex (SC), forms only between aligned pairs of homologous chromosomes. In the present study, we find that two closely related members of the him-3 gene family in Caenorhabditis elegans function as regulators of synapsis. HTP-1 functionally couples homolog alignment to its stabilization by synapsis by preventing the association of SC components with unaligned and immature chromosome axes; in the absence of the protein, nonhomologous contacts between chromosomes are inappropriately stabilized, resulting in extensive nonhomologous synapsis and a drastic decline in chiasma formation. In the absence of both HTP-1 and HTP-2, synapsis is abrogated per se and the early association of SC components with chromosomes observed in htp-1 mutants does not occur, suggesting a function for the proteins in licensing SC assembly. Furthermore, our results suggest that early steps of recombination occur in a narrow window of opportunity in early prophase that ends with SC assembly, resulting in a mechanistic coupling of the two processes to promote crossing over.

Finding and keeping your partner during meiosis.

HIM-3 is a meiosis-specific protein that localizes to the cores of chromosomes from the earliest stages of prophase I until the metaphase to anaphase I transition in Caenorhabditis elegans. him-3 mutations disrupt homolog alignment, synapsis, and recombination and we propose that the association of HIM-3 with chromosome axes is a critical event in meiotic chromosome morphogenesis that is required for the proper coordination of these processes. The presence of HIM-3-like proteins in other eukaryotes, some of which are known to be required for synapsis and recombination, suggests the existence of a conserved class of axis-associated proteins that function at the junction of essential meiotic processes.

A component of C. elegans meiotic chromosome axes at the interface of homolog alignment, synapsis, nuclear reorganization, and recombination.

A universal feature of meiotic prophase is the pairing of homologous chromosomes, a fundamental prerequisite for the successful completion of all subsequent meiotic events. HIM-3 is a Caenorhabditis elegans meiosis-specific non-cohesin component of chromosome axes that is required for synapsis. Our characterization of new him-3 alleles reveals previously unknown functions for the protein. HIM-3 is required for the establishment of initial contacts between homologs, for the nuclear reorganization characteristic of early meiotic prophase, and for the coordination of these events with synaptonemal complex (SC) assembly. Despite the absence of homolog alignment, we find that recombination is initiated efficiently, indicating that initial pairing is not a prerequisite for early steps of the recombination pathway. Surprisingly, RAD-51-marked recombination intermediates disappear with apparent wild-type kinetics in him-3 null mutants in which homologs are spatially unavailable for recombination, raising the possibility that HIM-3's presence at chromosome axes inhibits the use of sister chromatids as templates for repair. We propose that HIM-3 is a molecular link between multiple landmark events of meiotic prophase; it is critical for establishing chromosome identity by configuring homologs to facilitate their recognition while simultaneously imposing structural constraints that later promote the formation of the crossover essential for proper segregation.

A heterochromatin protein 1 homologue in Caenorhabditis elegans acts in germline and vulval development.

Proteins of the highly conserved heterochromatin protein 1 (HP1) family have been found to function in the dynamic organization of nuclear architecture and in gene regulation throughout the eukaryotic kingdom. In addition to being key players in heterochromatin-mediated gene silencing, HP1 proteins may also contribute to the transcriptional repression of euchromatic genes via the recruitment to specific promoters. To investigate the role played by these different activities in specific developmental pathways, we identified HP1 homologues in the genome of Caenorhabditis elegans and used RNA-mediated interference to study their function. We show that one of the homologues, HPL-2, is required for the formation of a functional germline and for the development of the vulva by acting in an Rb-related pathway. We suggest that, by acting as repressors of gene expression, HP1 proteins may fulfil specific functions in both somatic and germline differentiation processes throughout development.