Chakraborty Sharmistha, Pandita Raj K, Hambarde Shashank, Mattoo Abid R, Charaka Vijaya, Ahmed Kazi M, Iyer Swaminathan P, Hunt Clayton R, Pandita Tej K
Department of Radiation Oncology, Houston Methodist Cancer Center, The Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX 77030, USA.
Department of Radiation Oncology, Houston Methodist Cancer Center, The Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX 77030, USA.
iScience. 2018 Apr 27;2:123-135. doi: 10.1016/j.isci.2018.03.016.
The chromatin remodeling factor SMARCAD1, an SWI/SNF ATPase family member, has a role in 5' end resection at DNA double-strand breaks (DSBs) to produce single-strand DNA (ssDNA), a critical step for subsequent checkpoint and repair factor loading to remove DNA damage. However, the mechanistic details of SMARCAD1 coupling to the DNA damage response and repair pathways remains unknown. Here we report that SMARCAD1 is recruited to DNA DSBs through an ATM-dependent process. Depletion of SMARCAD1 reduces ionizing radiation (IR)-induced repairosome foci formation and DSB repair by homologous recombination (HR). IR induces SMARCAD1 phosphorylation at a conserved T906 by ATM kinase, a modification essential for SMARCAD1 recruitment to DSBs. Interestingly, T906 phosphorylation is also important for SMARCAD1 ubiquitination by RING1 at K905. Both these post-translational modifications are critical for regulating the role of SMARCAD1 in DNA end resection, HR-mediated repair, and cell survival after DNA damage.
染色质重塑因子SMARCAD1是SWI/SNF ATP酶家族成员，在DNA双链断裂（DSB）处的5'端切除中发挥作用，以产生单链DNA（ssDNA），这是后续检查点和修复因子加载以去除DNA损伤的关键步骤。然而，SMARCAD1与DNA损伤反应和修复途径偶联的机制细节仍不清楚。在此我们报告，SMARCAD1通过依赖ATM的过程被招募到DNA DSB处。SMARCAD1的缺失会减少电离辐射（IR）诱导的修复体焦点形成以及同源重组（HR）介导的DSB修复。IR通过ATM激酶在保守的T906位点诱导SMARCAD1磷酸化，这种修饰对于SMARCAD1招募到DSB至关重要。有趣的是，T906磷酸化对于RING1在K905位点对SMARCAD1进行泛素化也很重要。这两种翻译后修饰对于调节SMARCAD1在DNA末端切除、HR介导的修复以及DNA损伤后细胞存活中的作用都至关重要。
