Role of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) in double-strand break (DSB) mobility and repair

Abstract

DNA double-strand breaks (DSBs) are the most detrimental DNA lesions that threaten genome integrity and cell survival. To mitigate these threats, cells have evolved a sophisticated network of DNA damage responses (DDRs) to repair DSBs properly and efficiently. In addition to the activation of the DDR network, DSBs also become mobilised within the cell nucleus. DSB mobilisation facilitates DSB relocation and clustering, which in turn foster optimal DSB repair.

While emerging evidence reveals that nuclear actin filaments (nuclear F-actin) direct DSB movements for proper repair, the underlying mechanism that regulates this process remains to be explored. In this study, I have identified the DYRK1A-Spir1 axis as a regulatory pathway that fosters DSB mobility and repair. In the first part of my study, I demonstrated that DYRK1A docks at DSBs and promotes DSB repair. The kinase activity of DYRK1A is critical for DSB repair. Phosphoproteome profiling suggests that DYRK1A targets a cohort of actin regulators to control actin dynamics. Consistently, my subsequent experimental findings showed that DYRK1A enhances local actin polymerisation at DSBs, and that its kinase activity is also critical for DSB mobilisation. Furthermore, the role of DYRK1A in DSB mobilisation and repair requires the polymerisation ability of nuclear actin. Collectively, my findings indicate that DYRK1A supports DSB repair via nuclear F-actin-mediated DSB mobilisation.

In the second part of my study, I identified Protein Spire Homolog 1 (Spir1) as a downstream target of DYRK1A that assists DSB repair. I first revealed that Spir1 is enriched at DSBs, and Spir1 is critical for actin polymerisation at DSBs. Moreover, DYRK1A phosphorylates Spir1 at serine-482 (S482), and may drive efficient turnover of Spir1 at DSBs. Further experiments revealed that DYRK1A works together with Spir1 to promote DNA damage-induced F-actin assembly, as well as DSB repair.

Collectively, the findings mentioned unveiled DYRK1A as a molecular determinant to support DSB mobilisation and repair via nuclear actin organisation control.