STK19 is a DNA/RNA-binding protein critical for DNA damage repair and cell proliferation

Abstract

STK19 was originally identified as a manganese-dependent serine/threonine-specific protein kinase, but its function has been highly debated. Here, the crystal structure of STK19 revealed that it does not contain a kinase domain, but three intimately packed winged helix (WH) domains. The third WH domain mediated homodimerization and double-stranded DNA binding, both being important for its nuclear localization. STK19 participated in the nucleotide excision repair (NER) and mismatch repair (MMR) pathways by recruiting damage repair factors such as RPA2 and PCNA. STK19 also bound double-stranded RNA through the DNA-binding interface and regulated the expression levels of many mRNAs. Furthermore, STK19 knockdown cells exhibited very slow cell proliferation, which cannot be rescued by dimerization or DNA-binding mutants. Therefore, this work concludes that STK19 is highly unlikely to be a kinase but a DNA/RNA-binding protein critical for DNA damage repair (DDR) and cell proliferation. To prevent further confusions, we renamed this protein as TWH19 (Tandem Winged Helix protein formerly known as STK19).

Mutations found in cancer patients compromise DNA binding of the winged helix protein STK19

“…1 e). This is different from the conclusion of the recent paper 17 . The latter emphasized more about the capability of STK19 to form dimers, especially in the presence of DNA, which is still possible.…”

“…In the absence of a kinase domain, the current official protein and gene names of STK19 need to be changed to better reflect its identity. The same conclusion was achieved by another two independent studies 10 , 17 .

Figure 1 Overall structure of the human STK19 protein.

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“…In this study, we determined a 1.32 Å crystal structure of human STK19 protein, revealed that STK19 is a winged-helix (WH) protein instead of a kinase, and performed structural-guided analysis of the STK19 molecular function. In contrast to the conclusions from a recently published STK19 structure study 17 , we provide evidence that STK19 is a monomer in solution, and demonstrate mutations found in cancer patients, K186N, R200W, and R215W, significantly compromise STK19 DNA binding, with more mutations predicted to do so. Additionally, we point out that the DNA binding surface identified so far is different from the canonical nucleic acid binding site of the WH domain.…”

STK19 drives Transcription-Coupled Repair by stimulating repair complex stability, Pol II ubiquitylation and TFIIH recruitment

“…Based on limited sequence similarity to a tyrosine kinase and in vitro assays showing kinase activity to serine/threonine residues it was named STK19 [37][38][39] . However, recent data showed that the originally proposed 41 kDa STK19 form 36 was not expressed, but that the main STK19 gene product is 110 amino acid shorter and forms a 29 kDa protein that does not have detectable kinase activity 40,41 , resulting in its current nomenclature as "Inactive serine/threonine-protein kinase 19". STK19 was thus far mainly studied as it contained recurrent UV-induced melanoma driver mutations [42][43][44] .…”

“…STK19 was thus far mainly studied as it contained recurrent UV-induced melanoma driver mutations [42][43][44] . However, the functional consequence of the recurrent STK19 D89N mutation is controversial, as this mutation is not present in the coding region of the 29 kDa STK19 form 40,41,43 . Interestingly, recently a role for STK19 during the cellular response to transcription-blocking lesions (TBLs) has been suggested 28,41,45,46 .…”