MACROD2 Haploinsufficiency Impairs Catalytic Activity of PARP1 and Promotes Chromosome Instability and Growth of Intestinal Tumors

Abstract

ADP-ribosylation is an important posttranslational protein modification that regulates diverse biological processes, controlled by dedicated transferases and hydrolases. Here, we show that frequent deletions (∼30%) of the mono-ADP-ribosylhydrolase locus in human colorectal cancer cause impaired PARP1 transferase activity in a gene dosage-dependent manner. haploinsufficiency alters DNA repair and sensitivity to DNA damage and results in chromosome instability. Heterozygous and homozygous depletion of enhances intestinal tumorigenesis in mice and the growth of human colorectal cancer xenografts. deletion in sporadic colorectal cancer is associated with the extent of chromosome instability, independent of clinical parameters and other known genetic drivers. We conclude that acts as a haploinsufficient tumor suppressor, with loss of function promoting chromosome instability, thereby driving cancer evolution. Chromosome instability (CIN) is a hallmark of cancer. We identify deletion as a cause of CIN in human colorectal cancer. MACROD2 loss causes repression of PARP1 activity, impairing DNA repair. haploinsufficiency promotes CIN and intestinal tumor growth. Our results reveal as a major caretaker tumor suppressor gene..

(ADP-ribosyl)hydrolases: structure, function, and biology

“…Aberrant MacroD1 expression and gene fusions contribute to tumour pathology; e.g., in leukaemia, breast, gastric, liver, lung, and colorectal cancer (Imagama et al 2007;Shao et al 2015;Sakthianandeswaren et al 2018). Several lines of evidence indicate that MacroD1 is involved in several important signaling pathways: In breast cancer-derived MCF-7 cells, MacroD1 expression is induced by estrogenic hormones in an estrogen receptor alpha (ERα)-dependent manner and subsequently acts as a cofactor for ERα and the androgen receptor (Han et al 2007;Yang et al 2009).…”

The Controversial Roles of ADP-Ribosyl Hydrolases MACROD1, MACROD2 and TARG1 in Carcinogenesis

“…The authors argue that, as a cancer specific fragile site, the MACROD2 gene can be lost, but this fragility also allows for amplification in the specific case of ER-positive breast cancers treated with tamoxifen to incur resistance. A more recent study showed that, in approximately one-third of colorectal carcinomas investigated, heterozygous or homozygous losses were mapped within the MACROD2 gene in which the majority are intragenic microdeletions mapping to a region in exons 4 to 5 [111]. To test whether MACROD2 deficiency can promote tumourigenesis, MACROD2 knockout was introduced into an adenomatous polyposis coli protein (Apc) mouse model.…”

“…To test whether MACROD2 deficiency can promote tumourigenesis, MACROD2 knockout was introduced into an adenomatous polyposis coli protein (Apc) mouse model. Mutations in the APC tumour suppressor are a major driver of sporadic colorectal cancers, where it could be shown that even haploinsufficiency of MACROD2 leads to more and larger adenoma formation [111]. Furthermore, human cells transplanted into nude mice displayed increased tumour growth when lacking MACROD2, but a reduced tumour growth when MACROD2 was overexpressed [111].…”

“…Mutations in the APC tumour suppressor are a major driver of sporadic colorectal cancers, where it could be shown that even haploinsufficiency of MACROD2 leads to more and larger adenoma formation [111]. Furthermore, human cells transplanted into nude mice displayed increased tumour growth when lacking MACROD2, but a reduced tumour growth when MACROD2 was overexpressed [111]. The underlying mechanism was suggested to be impaired PARP1 activity in the MACROD2 -/cells, which leads to increased sensitivity of DNA damage and, ultimately, causes enhanced chromosomal instability [111,112].…”

Genome-wide association study in European patients with congenital heart disease identifies risk loci for transposition of the great arteries and anomalies of the thoracic arteries and veins and expression of discovered candidate genes in the developing heart

“…In the TGA subgroup, four SNPs with genome-wide significance mapped to MACROD2 which has been linked to adipogenesis and hypertension. 26,33 Microdeletions in this gene have been implicated as a cause of chromosomal instability in cancers 34 and de novo deletion of exon 5 causes Kabuki syndrome. 35 Chromosomal imbalance is also frequently seen in CHD patients with different morphologies [36][37][38][39] including TGA 40 but so far the MACROD2 locus was not associated with CHD.…”