Since the earliest observations of cells undergoing mitosis, it has been clear that there is an intimate relationship between the cell cycle and nuclear chromatin architecture. The nuclear envelope and chromatin undergo robust assembly and disassembly during the cell cycle, and transcriptional and post-transcriptional regulation of histone biogenesis and chromatin modification is controlled in a cell cycle-dependent manner. Chromatin binding proteins and chromatin modifications in turn influence the expression of critical cell cycle regulators, the accessibility of origins for DNA replication, DNA repair, and cell fate. In this review we aim to provide an integrated discussion of how the cell cycle machinery impacts nuclear architecture and vice-versa. We highlight recent advances in understanding cell cycle-dependent histone biogenesis and histone modification deposition, how cell cycle regulators control histone modifier activities, the contribution of chromatin modifications to origin firing for DNA replication, and newly identified roles for nucleoporins in regulating cell cycle gene expression, gene expression memory and differentiation. We close with a discussion of how cell cycle status may impact chromatin to influence cell fate decisions, under normal contexts of differentiation as well as in instances of cell fate reprogramming.

SUMMARYSUMOylation is a highly conserved post-translational modification shown to modulate target protein activity in a wide variety of cellular processes. Although the requirement for SUMO modification of specific substrates has received significant attention in vivo and in vitro, the developmental requirements for SUMOylation at the cell and tissue level remain poorly understood. Here, we show that in Drosophila melanogaster, both heterodimeric components of the SUMO E1-activating enzyme are zygotically required for mitotic progression but are dispensable for cell viability, homeostasis and DNA synthesis in non-dividing cells. Explaining the lack of more pleiotropic effects following a global block of SUMO conjugation, we further demonstrate that low levels of global substrate SUMOylation are detected in mutants lacking either or both E1 subunits. These results not only suggest that minimal SUMOylation persists in the absence of Aos1/Uba2, but also show that the process of cell division is selectively sensitive to reductions in global SUMOylation. Supporting this view, knockdown of SUMO or its E1 and E2 enzymes robustly disrupts proliferating cells in the developing eye, without any detectable effects on the development or differentiation of neighboring post-mitotic cells.

The Nucleoporin 98KD (Nup98) is a promiscuous translocation partner in hematological malignancies. Most disease models of Nup98 translocations involve ectopic expression of the fusion protein under study, leaving the endogenous Nup98 loci unperturbed. Overlooked in these approaches is the loss of one copy of normal Nup98 in addition to the loss of Nup96 – a second Nucleoporin encoded within the same mRNA and reading frame as Nup98, in translocations. Nup98 and 96 are also mutated in a number of other cancers, suggesting their disruption is not limited to blood cancers. We found that reducing Nup98-96 function in Drosophila melanogaster (where the Nup98-96 shared mRNA and reading frame is conserved) de-regulates the cell cycle. We find evidence of over-proliferation in tissues with reduced Nup98-96, counteracted by elevated apoptosis and aberrant signaling associated with chronic wounding. Reducing Nup98-96 function leads to defects in protein synthesis that trigger JNK signaling and contributes to hallmarks of tumorigenesis when apoptosis is inhibited. We suggest partial loss of Nup98-96 function in translocations could de-regulate protein synthesis leading to signaling that cooperates with other mutations to promote tumorigenesis.

The Nucleoporin 98KD (Nup98) is one of the most promiscuous translocation partners in hematological malignancies, contributing to at least 31 different truncation—fusion proteins. To date, nearly all disease models of Nup98 translocations involve ectopic expression of transgenes recapitulating the fusion protein under study, leaving the endogenous Nup98 loci unperturbed. Overlooked in these approaches is that translocation leads to the loss of one copy of normal Nup98 in addition to the loss of Nup96, a second Nucleoporin encoded within the same mRNA and reading frame as Nup98. Nup98 and 96 are also mutated in a number of other cancer types and are located near a tumor suppressor region known to be epigenetically silenced, suggesting that their disruption is not limited to blood cancers. We found that reducing Nup98—96 function via an RNAi approach in Drosophila melanogaster (where the Nup98—96 shared mRNA and reading frame gene structure is conserved) deregulates the cell cycle. We find evidence of overproliferation in Nup98—96 deficient tissues, counteracted by elevated apoptosis and aberrant Wingless and JNK signaling associated with chronic wound healing. When the knockdown of Nup98—96 is combined with inhibition of apoptosis, we see synergism leading to dramatic tissue overgrowth, consistent with a tumor suppressor function for endogenous Nup98 and 96. To understand how growth and proliferation become misregulated when Nup98—96 levels are reduced, we performed RNAseq and uncovered a gene expression signature consistent with defects in ribosome biogenesis. We found that reducing Nup 98 and 96 function limits nuclear export of the ribosome component RpL10A, leading to defects in protein synthesis. Defects in protein synthesis are sufficient to trigger JNK signaling that contributes to compensatory proliferation and hallmarks of tumorigenesis when apoptosis is inhibited. Based upon our data, we suggest that the partial loss of Nup98 and Nup96 function in translocations could de-regulate protein synthesis leading to stress signaling that cooperates with other mutations in cancer to promote tumorigenesis.