Self-inflicted DNA breaks in cell differentiation and cancer.

Self-inflicted DNA strand breaks are canonically linked with cell death pathways and the establishment of genetic diversity in immune and germline cells. Moreover, this form of DNA damage is an established source of genome instability in cancer development. However, recent studies indicate that nonlethal self-inflicted DNA strand breaks play an indispensable but underappreciated role in a variety of cell processes, including differentiation and cancer therapy responses. Mechanistically, these physiological DNA breaks originate from the activation of nucleases, which are best characterized for inducing DNA fragmentation in apoptotic cell death. In this review, we outline the emerging biology of one critical nuclease, caspase-activated DNase (CAD), and how directed activation or deployment of this enzyme can lead to divergent cell fate outcomes.

Chromatin Reorganization during Myoblast Differentiation Involves the Caspase-Dependent Removal of SATB2.

The induction of lineage-specific gene programs are strongly influenced by alterations in local chromatin architecture. However, key players that impact this genome reorganization remain largely unknown. Here, we report that the removal of the special AT-rich binding protein 2 (SATB2), a nuclear protein known to bind matrix attachment regions, is a key event in initiating myogenic differentiation. The deletion of myoblast SATB2 in vitro initiates chromatin remodeling and accelerates differentiation, which is dependent on the caspase 7-mediated cleavage of SATB2. A genome-wide analysis indicates that SATB2 binding within chromatin loops and near anchor points influences both loop and sub-TAD domain formation. Consequently, the chromatin changes that occur with the removal of SATB2 lead to the derepression of differentiation-inducing factors while also limiting the expression of genes that inhibit this cell fate change. Taken together, this study demonstrates that the temporal control of the SATB2 protein is critical in shaping the chromatin environment and coordinating the myogenic differentiation program.