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. 2023 Sep 7;24(18):13807. doi: 10.3390/ijms241813807

Figure 2.

Figure 2

TDP-43-mediated DNA repair: direct and indirect roles. Schematic diagrams of TPD-43 role in DSB repair. (A–C) Direct role of TDP-43 in DSB repair and its misregulation in ALS. (A) TDP-43 in DNA double-stranded break (DSB) repair. TDP-43 interaction with activated (phosphorylated) DNA damage repair (DDR) response factors (p-ATM, p-53BP1, p-H2AX = yH2AX) facilitates the NHEJ repair in neurons by supporting the recruitment and activity of the XLF/XRCC4/Lig4 complex [23]. (B) TDP-43 in transcription-coupled DSB (TC-DSB) repair. TDP-43 interacts with several key factors in the transcription-coupled repair (i.e., DHX9, COPS3/4, AQR, RFC, PARP1, XRCC1, TDP1, APEX1, Ku70/80, and condensin SMC3), and binds non-blocked dsDNA ends such as those created at DSB. It is also probably involved in the transcriptional silencing following DSB through its recruitment of SIRT-2 and subsequent H3K18 deacetylation, as evidenced in HeLa and MEFs cells [97] and in post-mitotic neuronal cells. The hypothetical recruitment of RNA helicase DDX5 with TDP-43 at R-loop by the Lnc530 to resolve their aberrant formation is still to be investigated in neurons and in the human. (C) TDP-43-related genome damage in ALS motor and cortical neurons and in differentiated neuronal SH-SY5Y cells. In presence of a mutant or mislocalized TDP-43, yH2AX levels are reduced, and the NHEJ complex (XLF/XRCC4/Lig4) is not recruited to damage sites for repair, resulting in an accumulation of damaged DNA and leading to neurodegeneration. (D) TDP-43 regulation of genes impacting DNA damage and repair. TDP-43 positively regulates Sirt1 and Poldip3 mRNA levels by binding to their 3′UTR, stabilizing them. Upon TPD-43 alterations, Sirt1 mRNA levels decrease and SIRT1-mediated deacetylation of Ku70 is reduced, lowering HR and NEHJ DSB repair. Likewise, a decrease in Poldip3 mRNA levels could reduce the DNA damage checkpoint and the resolution of R-loop. SIRT1 and POLDIP3 functions in the DSB response in mature neurons remain evasive. Different means by which functional TDP-43 acts against RTE activity at the chromatin level are listed, as well as the general negative consequences which RTE uncontrolled activity can have on the genome and transcriptome stability.