Sp1-dependent recruitment of the histone acetylase p300 to DSBs facilitates chromatin remodeling and recruitment of the NHEJ repair factor Ku70.

In response to DNA damage, most factors involved in damage recognition and repair are tightly regulated to ensure proper repair pathway choice. Histone acetylation at DNA double strand breaks (DSBs) by p300 histone acetyltransferase (HAT) is critical for the recruitment of DSB repair proteins to chromatin. Here, we show that phosphorylation of Sp1 by ATM increases its interaction with p300 and that Sp1-dependent recruitment of p300 to DSBs is necessary to modify the histones associated with p300 activity and NHEJ repair factor recruitment and repair.

DSB repair pathway choice is regulated by recruitment of 53BP1 through cell cycle-dependent regulation of Sp1.

Although many of the factors, epigenetic changes, and cell cycle stages that distinguish repair of double-strand breaks (DSBs) by homologous recombination (HR) from non-homologous end joining (NHEJ) are known, the underlying mechanisms that determine pathway choice are incompletely understood. Previously, we found that the transcription factor Sp1 is recruited to DSBs and is necessary for repair. Here, we demonstrate that Sp1 localizes to DSBs in G1 and is necessary for recruitment of the NHEJ repair factor, 53BP1.

Elevated telomere dysfunction in cells containing the African-centric Pro47Ser cancer-risk variant of TP53.

Subtelomeric transcription and chromatin can have a significant impact on telomere repeat maintenance and chromosome stability. We have previously found that tumor suppressor protein p53 (TP53) can bind to retrotransposon-like elements in a majority of human subtelomeres to regulate TERRA transcription and telomeric histone acetylation in response to DNA damage. TP53 also prevents the accumulation of γH2AX DNA-damage signaling at telomeres.

Caspase cleavage of transcription factor Sp1 enhances apoptosis.

Sp1 is a ubiquitous transcription factor that regulates many genes involved in apoptosis and senescence. Sp1 also has a role in the DNA damage response; at low levels of DNA damage, Sp1 is phosphorylated by ATM and localizes to double-strand break sites where it facilitates DNA double-strand-break repair. Depletion of Sp1 increases the sensitivity of cells to DNA damage, whereas overexpression of Sp1 can drive cells into apoptosis.

CTCF driven TERRA transcription facilitates completion of telomere DNA replication.

Telomere repeat DNA forms a nucleo-protein structure that can obstruct chromosomal DNA replication, especially under conditions of replication stress. Transcription of telomere repeats can initiate at subtelomeric CTCF-binding sites to generate telomere repeat-encoding RNA (TERRA), but the role of transcription, CTCF, and TERRA in telomere replication is not known. Here, we have used CRISPR/Cas9 gene editing to mutate CTCF-binding sites at the putative start site of TERRA transcripts for a class of subtelomeres.

Subtelomeric p53 binding prevents accumulation of DNA damage at human telomeres.

Telomeres and tumor suppressor protein TP53 (p53) function in genome protection, but a direct role of p53 at telomeres has not yet been described. Here, we have identified non-canonical p53-binding sites within the human subtelomeres that suppress the accumulation of DNA damage at telomeric repeat DNA. These non-canonical subtelomeric p53-binding sites conferred transcription enhancer-like functions that include an increase in local histone H3K9 and H3K27 acetylation and stimulation of subtelomeric transcripts, including telomere repeat-containing RNA (TERRA).

Sp1 and the 'hallmarks of cancer'.

For many years, transcription factor Sp1 was viewed as a basal transcription factor and relegated to a role in the regulation of so-called housekeeping genes. Identification of Sp1's role in recruiting the general transcription machinery in the absence of a TATA box increased its importance in gene regulation, particularly in light of recent estimates that the majority of mammalian genes lack a TATA box. In this review, we briefly consider the history of Sp1, the founding member of the Sp family of transcription factors.

Interplay between the cell cycle and double-strand break response in mammalian cells.

The cell cycle is intimately associated with the ability of cells to sense and respond to and repair DNA damage. Understanding how cell cycle progression, particularly DNA replication and cell division, are regulated and how DNA damage can affect these processes has been the subject of intense research. Recent evidence suggests that the repair of DNA damage is regulated by the cell cycle, and that cell cycle factors are closely associated with repair factors and participate in cellular decisions regarding how to respond to and repair damage.

Roles of ChlR1 DNA helicase in replication recovery from DNA damage.

The ChlR1 DNA helicase is mutated in Warsaw breakage syndrome characterized by developmental anomalies, chromosomal breakage, and sister chromatid cohesion defects. However, the mechanism by which ChlR1 preserves genomic integrity is largely unknown. Here, we describe the roles of ChlR1 in DNA replication recovery.

Sp1 facilitates DNA double-strand break repair through a nontranscriptional mechanism.

Sp1 is a ubiquitously expressed transcription factor that is phosphorylated by ataxia telangiectasia mutated kinase (ATM) in response to ionizing radiation and H(2)O(2). Here, we show by indirect immunofluorescence that Sp1 phosphorylated on serine 101 (pSp1) localizes to ionizing radiation-induced foci with phosphorylated histone variant γH2Ax and members of the MRN (Mre11, Rad50, and Nbs1) complex. More precise analysis of occupancy of DNA double-strand breaks (DSBs) by chromatin immunoprecipitation (ChIP) shows that Sp1, like Nbs1, resides within 200 bp of DSBs.