Checkpoint activation drives global gene expression changes in Drosophila nuclear lamina mutants

Abstract

The nuclear lamina (NL) lines the inner nuclear membrane. This extensive protein network organizes chromatin and contributes to the regulation of transcription, DNA replication and repair. Lap2-emerin-MAN1 domain (LEM-D) proteins are key members of the NL, representing proteins that connect the NL to the genome through shared interactions with the chromatin binding protein Barrier-to-autointegration factor (BAF). Functions of the LEM-D protein emerin and BAF are essential during Drosophila melanogaster oogenesis. Indeed, loss of either emerin or BAF blocks germ cell development and causes loss of germline stem cells, defects linked to deformation of NL structure and non-canonical activation of Checkpoint kinase 2 (Chk2). Here, we investigate contributions of emerin and BAF to gene expression in the ovary. Profiling RNAs from emerin and baf mutant ovaries revealed that nearly all baf mis-regulated genes were shared with emerin mutants, defining a set of NL-regulated genes. Strikingly, loss of Chk2 restored expression of most NL-regulated genes, identifying a large class of Chk2-dependent genes (CDGs). Nonetheless, some genes remained mis-expressed upon Chk2 loss, identifying a smaller class of emerin-dependent genes (EDGs). Properties of EDGs suggest a shared role for emerin and BAF in repression of developmental genes. Properties of CDGs demonstrate that Chk2 activation drives global mis-expression of genes in the emerin and baf mutant backgrounds. Notably, CDGs were found up-regulated in lamin-B mutant backgrounds. These observations predict that Chk2 activation might have a general role in gene expression changes found in NL-associated diseases, such as laminopathies.

Nuclear size rectification: A potential new therapeutic approach to reduce metastasis in cancer

“…Interestingly, ATM was among the targets of NSRs in PC-3 cells in the study by Tollis et al, as were two other cancer drug target candidates involved in DNA repair, CHK2 and CDK7 ( Krystof and Uldrijan, 2010 ; Garrett and Collins, 2011 ). Interestingly, CHK2 has been shown to mediate gene expression changes in response to mutations in nuclear lamina (NL) factors emerin and BAF in Drosophila ( Kitzman et al, 2022 ), indicating further crosstalk between NL and DNA damage responses.…”