MRG15 is a member of the mortality factor family of proteins that have been implicated in processes involving cell growth and aging and is found in at least two distinct chromatin-modifying complexes, a 5-subunit histone deacetylase (HDAC)-complex containing the Sin3 corepressor and the 11-subunit NuA4 histone acetyltransferase complex. At the molecular level, MRG15 has been implicated in targeting the Sin3 corepressor complex to histones enriched in H3 K36(me2/me3) found in actively transcribed chromatin via a N-terminus chromodomain. The MRG domain at its C-terminus is thought to link MRG15 with Pf1 and thereby to the Sin3 and HDAC proteins in the Sin3 complex. MRG domains are common to all the mortality factor proteins and although the structure of the MRG domain is known, there is no information about the nature of the targets and how it interacts with them.We have characterized the interaction of the MRG15 chromodomain with its cognate chromatin target and also that of the MRG15 MRG domain with Pf1. Our results indicate a surprisingly low affinity interaction between the chromodomain and its chromatin target, but a much stronger interaction between the MRG domain and Pf1; interestingly, other H3 methylated lysine peptides display comparable affinities to H3 K36(me2/me3). We have identified and characterized the MRG-interaction motif in Pf1 using a combination of mutagenesis, biochemical assays, informatics, and solution NMR; an analogous motif is also found in other MRG-domain interactors such as PALB2 and PAM14. The motif binds to MRG15 MRG with high affinity and competitively inhibits the oligomerization activity of MRG15 MRG.