ZNF524 directly interacts with telomeric DNA and supports telomere integrity

Abstract

Telomeres are nucleoprotein structures at the ends of linear chromosomes. In humans, they consist of TTAGGG repeats, which are bound by dedicated proteins such as the shelterin complex. This complex blocks unwanted DNA damage repair at telomeres, e.g. by suppressing non-homologous end joining (NHEJ) through its subunit TRF2. We here describe ZNF524, a zinc finger protein that directly binds telomeric repeats with nanomolar affinity and reveal the base-specific sequence recognition by co-crystallization with telomeric DNA. ZNF524 localizes to telomeres and specifically maintains the presence of the TRF2/RAP1 subcomplex at telomeres without affecting other shelterin members. Loss of ZNF524 concomitantly results in an increase in DNA damage signaling and recombination events. Overall, ZNF524 is a direct telomere-binding protein involved in the maintenance of telomere integrity.

Structural insights into the recognition of telomeric variant repeat TTGGGG by broad-complex, tramtrack and bric-à-brac - zinc finger protein ZBTB10

“…5 C ). Recently, we demonstrated that ZNF524 directly interacts with telomeric DNA and supports telomere integrity, with its ZF2 playing a vital role in telomeric DNA recognition ( 33 ). Furthermore, our recent X-ray structures of ZBTB7A ZF1–4 in complex with the −200 sequence element of the γ-globin gene promoter reveal that its ZF4 recognizes a 3′ C:G nucleotide triplet ( 34 ).…”

ZBTB48 is a pioneer factor regulating B-cell-specific CIITA expression

“…Here, the RxxHxxR motif of ZnF11 recognizes G10G11G12 with Arg589, His592 and Arg595 forming a bidentate hydrogen bond interaction with G12, G11 and G10, respectively. This is equivalent to the interaction of both ZBTB48 and ZNF524 with telomeric repeats 32 and ZBTB10 with the telomeric variant repeat TTGGGG 33 (Figure 2C). However, in contrast to the co-crystal structure with telomeric DNA 31 , ZnF10 does not lie outside of the CIITA e.2 DNA duplex but rather interacts with the phosphate backbone along the major groove (Figure 2B, Supplementary Figure 1).…”